Processes for preparing antiviral compounds

ABSTRACT

The present disclosure provides processes for the preparation of a compound of formula: 
     
       
         
         
             
             
         
       
     
     which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalApplication No. 62/010,813, filed Jun. 11, 2014, which is herebyincorporated by reference in its entirety.

FIELD

The present disclosure relates generally to the field of organicsynthetic methodology for the preparation of antiviral compounds and thesynthetic intermediates prepared thereby.

BACKGROUND

Hepatitis C is recognized as a viral disease of the liver. Althoughdrugs targeting the liver are in wide use and have shown effectiveness,toxicity and other side effects have limited their usefulness.Inhibitors of hepatitis C virus (HCV) are useful to limit theestablishment and progression of infection by HCV as well as indiagnostic assays for HCV.

SUMMARY

The compound of Formula (A) is known to exhibit antiviral properties (WO2013/075029). Processes suitable for its production are disclosedherein.

The present disclosure provides processes for making a compound offormula (A):

or a salt or solvate thereof.

In one embodiment, provided is a process for preparing a compound offormula (A):

or a salt or solvate thereof, comprising the steps of:

(a) contacting a compound of formula (I), stereoisomer thereof, ormixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G),stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G) with a compound of formula(H) or salt thereof:

under conditions sufficient to yield a compound of formula (B),stereoisomer thereof, or mixture of stereoisomers thereof:

(c) cyclizing a compound of formula (B) under conditions sufficient toyield a compound of formula (C):

(d) dehydrogenating the compound of formula (C) under conditionssufficient to yield a compound of formula (D):

(e) deprotecting the compound of formula (D) under conditions sufficientto yield a compound of formula (E) or a salt thereof:

and

(f) contacting the compound of formula (E) with a compound of formula(F):

under conditions sufficient to yield a compound of formula (A),

wherein PG is an amine protecting group, X and Y are each independentlyselected from the group consisting of halo, —OSO₂R, —OP(O)OR, and—OP(O)(OR)₂, and R is alkyl, haloalkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl.

In another embodiment, provided is a process for preparing a compound offormula (A):

or a salt or solvate thereof, comprising the steps of:

(a) contacting a compound of formula (I-a), stereoisomer thereof, ormixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G′),stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G′) with a compound of formula(H) or salt thereof:

under conditions sufficient to yield a compound of formula (B),stereoisomer thereof, or mixture of stereoisomers thereof:

(c) cyclizing the compound of formula (B) under conditions sufficient toyield a compound of formula (C):

(d) dehydrogenating the compound of formula (C) under conditionssufficient to yield a compound of formula (D):

(e) deprotecting the compound of formula (D) under conditions sufficientto yield a compound of formula (E) or a salt thereof:

and

(f) contacting the compound of formula (E) with a compound of formula(F):

under conditions sufficient to yield a compound of formula (A), whereinPG is an amine protecting group.

Also provided herein is a process for preparing a compound of formula(D):

comprising

(a) contacting a compound of formula (I), stereoisomer thereof, ormixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G),stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G) with a compound of formula(H) or salt thereof:

under conditions sufficient to yield a compound of formula (B),stereoisomer thereof, or mixture of stereoisomers thereof:

(c) cyclizing a compound of formula (B) under conditions sufficient toyield a compound of formula (C):

and

(d) dehydrogenating a compound of formula (C) under conditionssufficient to yield a compound of formula (D),

wherein PG is an amine protecting group, X and Y are each independentlyselected from the group consisting of halo, —OSO₂R, —OP(O)OR, and—OP(O)(OR)₂, and R is alkyl, haloalkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl.

Also provided herein is a process for preparing a compound of formula(C):

comprising

(a) contacting a compound of formula (I), stereoisomer thereof, ormixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G),stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G) with a compound of formula(H) or salt thereof:

under conditions sufficient to yield a compound of formula (B),stereoisomer thereof, or mixture of stereoisomers thereof:

and

(c) cyclizing a compound of formula (B) under conditions sufficient toyield a compound of formula (C),

wherein PG is an amine protecting group, X and Y are each independentlyselected from the group consisting of halo, —OSO₂R, —OP(O)OR, and—OP(O)(OR)₂, and R is alkyl, haloalkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl.

In another embodiment, provided is a process for preparing a compound offormula (I-a), stereoisomer, or mixture of stereoisomers thereof:

comprising the steps of:

(a) cyclizing a compound of formula (L):

under conditions sufficient to yield a compound of formula (K):

and

(b) brominating the compound of formula (K) under conditions sufficientto yield a compound of formula (I-a),

wherein Z is hydrogen, halo, —OSO₂R¹, —BF₃ ⁻, —B(OR²)₂, —CO₂H, or —NR¹ ₃wherein R¹ is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl, and R² is alkyl.

Also provided are processes for preparing a compound of formula (K):

comprising reacting a compound of formula (O):

under conditions sufficient to yield a compound of formula (K).

In another embodiment, provided is a process for preparing a compound offormula (K):

comprising hydrolyzing a compound of formula (P):

wherein R⁷ is alkyl, under conditions sufficient to yield a compound offormula (K).

In another embodiment, provided is a process for preparing a compound offormula (K):

comprising derivatizing a compound of formula (Q):

under conditions sufficient to yield the compound of formula K.

In one embodiment, a compound of formula (R):

is prepared by (a) cyclizing a compound of formula (U):

under conditions sufficient to yield the compound of formula (V):

and

(b) contacting the compound of formula (V) with an acid under conditionssufficient to yield the complex of formula (R), wherein PG is an amineprotecting group and R⁴ is an optionally substituted alkyl or optionallysubstituted aryl. In some embodiments, salts of (R) may be synthesizedusing certain acids such as para-toluenesulfonic acid, camphor sulfonicacid, methane sulfonic acid, benzene sulfonic acid, or p-bromobenzenesulfonic acid, among others. In particular embodiments R⁴ is alkyl andin more particular embodiments R⁴ is ethyl.

In one specific embodiment, provided is a process for preparing a saltof (R) wherein R⁴ is ethyl which is a complex of formula (R-a):

comprising the steps of:

(a) cyclizing a compound of formula (U′):

under conditions sufficient to yield the compound of formula (V′):

and

(b) contacting the compound of formula (V′) with para-toluenesulfonicacid, wherein PG is an amine protecting group, under conditionssufficient to yield the complex of formula (R-a).

Also provided herein is a process for preparing a compound of formula(J) or salt thereof:

comprising the steps of:

(a) contacting a compound of formula (W):

with a hydroboration reagent under conditions sufficient to yield acompound of formula (X):

(b) methylating the compound of formula (X) under conditions sufficientto yield a compound of formula (Y):

and

(c) resolving the compound of formula (Y) under conditions sufficient toyield a compound of formula (J), wherein PG is an amine protecting groupand PG¹ is a carboxylic acid protecting group.

In other embodiments, the disclosure provides intermediate compoundsthat are useful in the processes described herein. Thus, for instance,one embodiment is a compound of the formula L:

wherein Z is hydrogen, halo, —OSO₂R¹, —BF₃ ⁻, —B(OR²)₂, —CO₂H, or —NR¹ ₃wherein R¹ is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl, and R² is alkyl.

Also provided herein are compounds of formula (Q):

The inventions of this disclosure are described throughout. In addition,specific embodiments are as disclosed herein.

DETAILED DESCRIPTION Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms, or from 1to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbonatoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “substituted alkyl” refers to:

-   -   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5        substituents, (in some embodiments, 1, 2 or 3 substituents)        selected from the group consisting of alkenyl, alkynyl, alkoxy,        cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl,        acylamino, acyloxy, amino, substituted amino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,        thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,        heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,        aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,        heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —S(O)-alkyl,        —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,        —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl,        —S(O)₂-heterocyclyl, —S(O)₂-aryl and —S(O)₂-heteroaryl. Unless        otherwise constrained by the definition, all substituents may        optionally be further substituted by 1, 2 or 3 substituents        chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,        aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted        amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and        —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and        n is 0, 1 or 2; or    -   2) an alkyl group as defined above that is interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from        oxygen, sulfur and NR^(a), where R^(a) is chosen from hydrogen,        alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,        heteroaryl and heterocyclyl. All substituents may be optionally        further substituted by alkyl, alkenyl, alkynyl, carboxy,        carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,        amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,        heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or        heteroaryl and n is 0, 1 or 2; or    -   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5        substituents as defined above and is also interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halogen groups. For example, “C₁₋₃ haloalkyl” refers to an alkylgroup having from 1 to 3 carbon atoms covalently bonded to from 1 to 7,or from 1 to 6, or from 1 to 3, halogen(s), where alkyl and halogen aredefined herein. In some embodiments, C₁₋₃ haloalkyl includes, by way ofexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl,3,3,3-trifluoropropyl, 3,3-difluoropropyl, 3-fluoropropyl.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents), as defined for substituted alkyl or a lower alkyl groupas defined above that is interrupted by 1, 2, 3, 4 or 5 atoms as definedfor substituted alkyl or a lower alkyl group as defined above that hasboth 1, 2, 3, 4 or 5 substituents as defined above and is alsointerrupted by 1, 2, 3, 4 or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in some embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, in some embodiments, having 1,2, 3, 4, 5 or 6 carbon atoms.

The term “substituted alkylene” refers to an alkylene group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkoxy” refers to the group R—O—, where R is alkyl or —Y—Z, inwhich Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyland alkynyl are as defined herein. In some embodiments, alkoxy groupsare alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term “lower alkoxy” refers to the group R—O— in which R isoptionally substituted lower alkyl. This term is exemplified by groupssuch as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,t-butoxy, n-hexyloxy, and the like.

The term “substituted alkoxy” refers to the group R—O—, where R issubstituted alkyl or —Y—Z, in which Y is substituted alkylene and Z issubstituted alkenyl or substituted alkynyl, where substituted alkyl,substituted alkenyl and substituted alkynyl are as defined herein.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃), and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ringor multiple condensed rings. Such cycloalkyl groups include, by way ofexample, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclooctyl and the like or multiple ring structures such asadamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to whichis fused an aryl group, for example indanyl, and the like, provided thatthe point of attachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “substituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in some embodiments, 1, 2 or 3 substituents), selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. The term “substituted cycloalkyl”also includes cycloalkyl groups wherein one or more of the annularcarbon atoms of the cycloalkyl group has an oxo group bonded thereto. Inaddition, a substituent on the cycloalkyl or cycloalkenyl may beattached to the same carbon atom as, or is geminal to, the attachment ofthe substituted cycloalkyl or cycloalkenyl to the 6,7-ring system.Unless otherwise constrained by the definition, all substituents mayoptionally be further substituted by 1, 2 or 3 substituents chosen fromalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) isalkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “cycloalkoxy” refers to the group cycloalkyl-O—.

The term “substituted cycloalkoxy” refers to the group substitutedcycloalkyl-O—.

The term “cycloalkenyloxy” refers to the group cycloalkenyl-O—.

The term “substituted cycloalkenyloxy” refers to the group substitutedcycloalkenyl-O—.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In some embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (in some embodiments, 1, 2 or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,and/or oxygen within the ring. In some embodiments, the heterocyclyl,”“heterocycle,” or “heterocyclic” group is linked to the remainder of themolecule through one of the heteroatoms within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)— heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. In addition, a substituent on theheterocyclic group may be attached to the same carbon atom as, or isgeminal to, the attachment of the substituted heterocyclic group to the6,7-ring system. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Examplesof heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, andthe like.

The term “heterocyclooxy” refers to the group —O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic to the terms “aromatic heteroaryl” and“partially saturated heteroaryl”. The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine.

The term “partially saturated heteroaryl” refers to a heteroaryl havinga structure equivalent to an underlying aromatic heteroaryl which hashad one or more double bonds in an aromatic ring of the underlyingaromatic heteroaryl saturated. Examples of partially saturatedheteroaryls include dihydropyrrole, dihydropyridine, chroman,2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selectedfrom the group consisting alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy,amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridylor furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazoleor benzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “benzyl” refers to the group —CH₂—C₆H₅

The term “amino” refers to the group —NH₂.

The term “amine” refers to substituted amino, alkyl amine, dialkylamine,or trialkyl amine groups.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen or a group -Y-Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkyl amine” refers to R—NH₂ in which R is optionallysubstituted alkyl.

The term “dialkyl amine” refers to R—NHR in which each R isindependently an optionally substituted alkyl.

The term “trialkyl amine” refers to NR₃ in which each R is independentlyan optionally substituted alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group

The term “nitro” refers to a group —NO₂.

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano or —S(O)_(n)R^(a), in which R^(a) is alkyl,aryl or heteroaryl and n is 0, 1 or 2.

The term “acyl” denotes the group —C(O)R, in which R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “acyl halide” denotes the group —C(O)RX, in which R ishydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. X is ahalide group. The term “halide” halide ion refers to a halogen atombearing a negative charge. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the group —OC(O)—R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkoxycarbonylamino” refers to the group —N(R^(d))C(O)OR inwhich R is alkyl and R^(d) is hydrogen or alkyl. Unless otherwiseconstrained by the definition, each alkyl may optionally be furthersubstituted by 1, 2 or 3 substituents selected from the group consistingof alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in whichR^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonylamino” refers to the group —NR^(c)C(O)NRR,wherein R^(c) is hydrogen or alkyl and each R is hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “thiol” refers to the group —SH.

The term “thiocarbonyl” refers to a group ═S.

The term “alkylthio” refers to the group —S-alkyl.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heterocyclylthio” refers to the group —S-heterocyclyl.

The term “arylthio” refers to the group —S-aryl.

The term “heteroarylthio” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide”refers to a group —S(O)R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “aminosulfonyl” refers to the group —S(O)₂NRR, wherein each Ris independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “hydroxy” or “hydroxyl” refers to the group —OH.

The term “hydroxyamino” refers to the group —NHOH.

The term “alkoxyamino” refers to the group —NHOR in which R isoptionally substituted alkyl.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

The term “hydroboration reagent” refers to a reagent that contains boronand can be used during a hydroboration reaction. Non-limiting examplescan be BH₃-THF, 9-borabicyclo[3.3.1]nonane (“9-BBN”), catecholborane,and disiamylborane.

The term “reagent” refers to a substance or compound that can be addedto bring about a chemical reaction.

The term “oxidant” refers to a compound that has a carbon that can gainelectron density from another compound in a chemical reaction.

The term “amine reagent” refers to a compound that has nitrogen.

The term “additive” can refer to a compound that can be added to achemical reaction.

The term “coupling reagent” or “coupling agent” refers to a compoundthat aids in bringing about a reaction to couple one compound to anothercompound.

The term “organic base” is an organic compound that acts as a base.

The term “organic acid” is an organic compound that acts as an acid.

The term “brominating reagent” or “brominating agent” refers to acompound that can be added to carry out a bromination reaction.

The term “borohydride reagent” refers to a borohydride compound, such assodium triacetoxyborohydride, sodium borohydrodride, or sodiumtripropionoxyborohydride.

The term “complex” refers to a formation resulting from the interactionbetween a molecule and a second molecule.

A “leaving group” includes a molecular fragment that can depart with apair of electrons from a covalent bond to the reacting carbon atomduring a chemical reaction.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “loweralkyl-substituted phenyl”, where the attachment sites are not explicit,may have any available site of the lower alkyl group attached to anyavailable site of the phenyl group. In this regard, an “available site”is a site of the group at which a hydrogen of the group may be replacedwith a substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. Also not included areinfinite numbers of substituents, whether the substituents are the sameor different. In such cases, the maximum number of such substituents isthree. Each of the above definitions is thus constrained by a limitationthat, for example, substituted aryl groups are limited to -substitutedaryl-(substituted aryl)-substituted aryl.

A compound of a given formula is intended to encompass the compounds ofthe disclosure, and the pharmaceutically acceptable salts,pharmaceutically acceptable esters, isomers, tautomers, solvates,isotopes, hydrates, polymorphs, and prodrugs of such compounds.Additionally, the compounds of the disclosure may possess one or moreasymmetric centers, and can be produced as a racemic mixture or asindividual enantiomers or diastereoisomers. The number of stereoisomerspresent in any given compound of a given formula depends upon the numberof asymmetric centers present (there are 2^(n) stereoisomers possiblewhere n is the number of asymmetric centers). The individualstereoisomers may be obtained by resolving a racemic or non-racemicmixture of an intermediate at some appropriate stage of the synthesis orby resolution of the compound by conventional means. The individualstereoisomers (including individual enantiomers and diastereoisomers) aswell as racemic and non-racemic mixtures of stereoisomers areencompassed within the scope of the present disclosure, all of which areintended to be depicted by the structures of this specification unlessotherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

Some of the compounds exist as “tautomeric isomers” or “tautomers.”Tautomeric isomers are in equilibrium with one another. For example,amide containing compounds may exist in equilibrium with imidic acidtautomers. Regardless of which tautomer is shown, and regardless of thenature of the equilibrium among tautomers, the compounds are understoodby one of ordinary skill in the art to comprise both amide and imidicacid tautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.Non-limiting examples of amide-comprising and imidic acid-comprisingtautomers are shown below:

The term “polymorph” refers to different crystal structures of acrystalline compound. The different polymorphs may result fromdifferences in crystal packing (packing polymorphism) or differences inpacking between different conformers of the same molecule(conformational polymorphism).

The term “solvate” refers to a complex formed by the combining of acompound and a solvent.

The term “hydrate” refers to the complex formed by the combining of acompound and water.

The term “prodrug” refers to compounds that include chemical groupswhich, in vivo, can be converted and/or can be split off from theremainder of the molecule to provide for the active drug, apharmaceutically acceptable salt thereof or a biologically activemetabolite thereof.

Any formula or structure given herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes compounds in which from 1 to n hydrogensattached to a carbon atom is/are replaced by deuterium, in which n isthe number of hydrogens in the molecule. Such compounds exhibitincreased resistance to metabolism and are thus useful for increasingthe half life of any compound of Formula I when administered to amammal. See, for example, Foster, “Deuterium Isotope Effects in Studiesof Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Suchcompounds are synthesized by means well known in the art, for example byemploying starting materials in which one or more hydrogens have beenreplaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base “salts” by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. In some cases, the “salt” ofa given compound is a pharmaceutically acceptable salt. The term“pharmaceutically acceptable salt” of a given compound refers to saltsthat retain the biological effectiveness and properties of the givencompound, and which are not biologically or otherwise undesirable.

Base addition salts can be prepared from inorganic and organic bases.Salts derived from inorganic bases include, by way of example only,sodium, potassium, lithium, ammonium, calcium and magnesium salts. Saltsderived from organic bases include, but are not limited to, salts ofprimary, secondary and tertiary amines, such as alkyl amines, dialkylamines, trialkyl amines, substituted alkyl amines, di(substituted alkyl)amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines,trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl)amines, tri(substituted alkenyl) amines, cycloalkyl amines,di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkylamines, disubstituted cycloalkyl amine, trisubstituted cycloalkylamines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)amines, substituted cycloalkenyl amines, disubstituted cycloalkenylamine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines,triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclicamines, mixed di- and tri-amines where at least two of the substituentson the amine are different and are selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,heteroaryl, heterocyclic, and the like. Also included are amines wherethe two or three substituents, together with the amino nitrogen, form aheterocyclic or heteroaryl group. Amines are of general structureN(R³⁰)(R³¹)(R³²), wherein mono-substituted amines have 2 of the threesubstituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substitutedamines have 1 of the three substituents on nitrogen (R³⁰, R³¹ and R³²)as hydrogen, whereas tri-substituted amines have none of the threesubstituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen. R³⁰, R³¹ andR³² are selected from a variety of substituents such as hydrogen,optionally substituted alkyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocyclyl and the like. The above-mentioned aminesrefer to the compounds wherein either one, two or three substituents onthe nitrogen are as listed in the name. For example, the term“cycloalkenyl amine” refers to cycloalkenyl-NH₂, wherein “cycloalkenyl”is as defined herein. The term “diheteroarylamine” refers toNH(heteroaryl)₂, wherein “heteroaryl” is as defined herein and so on.Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike. Acid addition salts may be prepared from inorganic and organicacids. Salts derived from inorganic acids include hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Salts derived from organic acids include acetic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and thelike.

The term “reaction conditions” is intended to refer to the physicaland/or environmental conditions under which a chemical reactionproceeds. Examples of reaction conditions include, but are not limitedto, one or more of following: reaction temperature, solvent, pH,pressure, reaction time, mole ratio of reactants, the presence of a baseor acid, or catalyst, radiation, etc. Reaction conditions may be namedafter the particular chemical reaction in which the conditions areemployed, such as, coupling conditions, hydrogenation conditions,acylation conditions, reduction conditions, etc. Reaction conditions formost reactions are generally known to those skilled in the art or can bereadily obtained from the literature. Exemplary reaction conditionssufficient for performing the chemical transformations provided hereincan be found throughout, and in particular, the examples below. It isalso contemplated that the reaction conditions can include reagents inaddition to those listed in the specific reaction.

The term “reducing agent” refers to the addition of hydrogen to amolecule. Exemplary reducing agents include hydrogen gas (H₂) andhydride reagents such as borohydrides, lithium aluminium hydride,diisobutylaluminium hydride (DIBAL-H) and lithium triethylborohydride.

The term “protecting group” refers to a moiety of a compound that masksor alters the properties of a functional group or the properties of thecompound as a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion.

The term “deprotecting” refers to removing the protecting group.

The term “amine protecting group” refers to a chemical moiety which isadded to, and later removed from, an amine functionality to obtainchemoselectivity in a subsequent chemical reaction. Suitable nitrogenprotecting groups include carbobenzyloxy (Cbz) (removed byhydrogenolysis), p-methoxybenzyl carbonyl (Moz or MeOZ) (removed byhydrogenolysis), tert-butyloxycarbonyl (Boc) (removed by concentratedstrong acids, such as HCl or trifluoroacetic acid, or by heating),9-fluorenylmethyloxycarbonyl (FMOC) (removed by base, such aspiperidine), acetyl (Ac) (removed by treatment with a base), benzoyl(Bz) (removed by treatment with a base, most often with aqueous orgaseous ammonia or methylamine), benzyl (Bn) (removed byhydrogenolysis), a carbamate (removed by acid and mild heating),p-methoxybenzyl (PMB) (removed by hydrogenolysis), 3,4-dimethoxybenzyl(DMPM) (removed by hydrogenolysis), p-methoxyphenyl (PMP) (removed byammonium cerium(IV) nitrate), a succinimide (i.e., a cyclic imide)(removed by treatment with a base), tosyl (Ts) (removed by concentratedacid and strong reducing agents), and other sulfonamides (Nosyl and Nps)(removed by samarium iodide, tributyltin hydride, etc.).

The term “carboxylic acid protecting group” refers to a chemical moietywhich is added to, and later removed from, a carboxylic acidfunctionality to obtain chemoselectivity in a subsequent chemicalreaction. Suitable carboxylic acid protecting groups include methylesters (removed by acid or base), benzyl esters (removed byhydrogenolysis), tert-butyl esters (removed by acid, base, and somereductants), silyl esters (removed by acid, base, and organicmetallicreagents), orthoesters (removed by mild aqueous acid to form esters,which can be removed according to the ester's properties), and oxazoline(removed at pH<1 or pH>12 with heat).

The term “succinimide” refers to a cyclic imide, and may be monocyclic,bicyclic (e.g., phthalimides) or polycyclic, and may further beoptionally substituted. Non limiting examples include N-pthalimide,N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide,N-dithiasuccinimide, N-2,3-diphenylmaleimide, andN-2,3-dimethylmaleimide.

The term “catalyst” refers to a chemical substance that enables achemical reaction to proceed at a usually faster rate or under differentconditions (such as at a lower temperature) than otherwise possible.

In addition, abbreviations as used herein have respective meanings asfollows:

2-MeTHF 2-methyltetrahydrofuran 9-BBN 9-borabicyclo[3.3.1]nonane AcAcetate aq Aqueous Boc tert-Butoxycarbonyl BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate brs Broadsinglet Bu Butyl CDI Carbonyldiimidazole CDMT2-chloro-4,6-bis[3-(perfluorohexyl)propyloxy]- 1,3,5-triazine compComplicated conc. Concentrated COMU (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbeniumhexafluorophosphate d Doublet Dba dibenzylideneacetone DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DCCN,N′-Dicyclohexylcarbodiimide dd Doublet of doublets DMAcDimethylacetamide DMAP 4-Dimethylaminopyridine DMF DimethylformamideDMSO Dimethylsulfoxide EDC/EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Equiv Equivalents Et Ethyl EtOAc Ethylacetate EtOH Ethanol g Gram h Hour HATU1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HOBt HydroxybenzotriazoleHPLC High-pressure liquid chromatography Hz Hertz iPr Isopropyl JCoupling constant LCMS Liquid chromatography-mass spectrometry mMultiplet M Molar m/z Mass to charge Me Methyl MeOH Methanol MEK Methylethyl ketone mg Milligram MHz Mega hertz MIBK Methyl isobutyl ketone mLMilliliter mmol Millimole MTBE Methyl-tert-butyl ether NMMN-Methylmorpholine NMP N-Methyl-2-pyrrolidone NMR Nuclear magneticresonance Oxyma Ethyl 2-Cyano-2-(hydroxyimino)acetate Ph Phenyl PrPropyl PSI/psi Pound-force per square inch Py Pyridine PyBOPbenzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphatePyClOP Chlorotripyrrolidinophosphonium hexafluorophosphate s Singlet tTriplet T3P Propylphosphonic Anhydride TBDMS Tert-butyldimethylsilyl TBSTert-butyldimethylsilyl TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate t-Bu tert-Butyl TEMPO(2,2,6,6-Tetramethylpiperidin-1-yl)oxy TFA Trifluoroacetic acid THFTetrahydrofuran TLC Thin layer chromatography Ts Tosyl vol Volume wtWeight Δ Chemical shift μL Microliter

Processes

As described generally above, the disclosure provides in someembodiments processes for making a compound of formula (A).

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemesdescribed below. It will be apparent given the description herein thatthe general schemes may be altered by substitution of the startingmaterials with other materials having similar structures to result inproducts that are correspondingly different. Descriptions of synthesesfollow to provide numerous examples of how the starting materials mayvary to provide corresponding products. Given a desired product forwhich the substituent groups are defined, the necessary startingmaterials generally may be determined by inspection. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodiments ofthe present disclosure, inspection of the structure of the compound tobe synthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5^(th) Edition,2001), and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present disclosure are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113, 3)283-302). Racemic mixtures of chiral compounds of the disclosure can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched substrate. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

Scheme 1 represents an exemplary synthesis of compound of formula (A)and can be carried out according to the embodiments described herein.

In some embodiments, X and Y may be various moieties as discussed below.The particular reaction conditions and reagents employed in Scheme 1 arediscussed below.

In one embodiment, the present disclosure provides for a process forpreparing a compound of formula (A):

or a salt or solvate thereof, comprising the steps of:

(a) contacting a compound of formula (I), stereoisomer thereof, ormixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G),stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G) with a compound of formula(H) or salt thereof:

under conditions sufficient to yield a compound of formula (B),stereoisomer thereof, or mixture of stereoisomers thereof:

(c) cyclizing a compound of formula (B) under conditions sufficient toyield a compound of formula (C):

(d) dehydrogenating the compound of formula (C) under conditionssufficient to yield a compound of formula (D):

(e) deprotecting the compound of formula (D) under conditions sufficientto yield a compound of formula (E) or a salt thereof:

and

(f) contacting the compound of formula (E) with a compound of formula(F):

under conditions sufficient to yield a compound of formula (A),

wherein PG is an amine protecting group, X and Y are each independentlyselected from the group consisting of halo, —OSO₂R, —OP(O)OR, and—OP(O)(OR)₂, wherein R is alkyl, haloalkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl.

In some embodiments, the substituted aryl may be an aryl having one ormore substituents, such as alkyl, alkoxy, hydroxyl, nitro, halogen, andothers as discussed above.

In an embodiment, X is bromo and Y is bromo.

In certain embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of dichloromethane,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,dimethylformamide, acetone, methyl ethyl ketone (“MEK”), and methylisobutyl ketone (“MIBK”). In some embodiments, the reaction conditionsof step (a) comprise a temperature of from about 10° C. to about 60° C.or from about 10° C. to about 30° C.

In some embodiments, the reaction conditions of step (a) comprise aphosphate salt or a carbonate salt. In certain embodiments, thephosphate salt includes but is not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄,and Na₃PO₄. In some embodiments, the carbonate salt includes but is notlimited to Na₂CO₃, Cs₂CO₃, and NaHCO₃.

In certain embodiments, the compound of formula (J) is a potassium,sodium, or cesium salt.

In certain embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, dichloromethane, toluene, isopropyl acetate,ethyl acetate, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, acetone,MEK, MIBK, and a mixture thereof. In certain embodiments, the reactionconditions of step (b) comprise a temperature of from about 40° C. toabout 60° C. or from about 40° C. to about 50° C.

In some embodiments, the reaction conditions of step (b) comprise aphosphate salt or a carbonate salt. In certain embodiments, thephosphate salt includes but is not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄,and Na₃PO₄. In some embodiments, the carbonate salt includes but is notlimited to Na₂CO₃, Cs₂CO₃, Li₂CO₃, CsHCO₃, K₂CO₃, KHCO₃ and NaHCO₃. Incertain embodiments, one or more phase transfer reagents may be used toassist with the reaction.

In certain embodiments, the compound of formula (H) is a potassium, asodium, or a cesium salt.

In some embodiments, the reaction conditions of step (c) comprises anamine reagent, wherein the amine reagent comprises ammonium acetate,hexamethyldisilzane, ammonia, ammonium formate, ammonium propionate,ammonium hexanoate, or ammonium octanoate.

In certain embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of toluene, xylene, analcohol, and a mixture thereof. In certain embodiments, the reactionconditions of step (c) comprise a temperature of from about 60° C. toabout 110° C. or from about 85° C. to about 95° C. In some embodiments,the alcohol can be isopropanol, 1-propanol, 1-butanol, 2-butanol,2-methoxyethanol, or a glycol, such as ethylene glycol or propyleneglycol. In some embodiments, the reaction condition comprises a mixtureof toluene and 2-butanol or isopropanol. In some embodiments, water isremoved during the process.

In certain embodiments, the reaction conditions of step (d) comprise anoxidant. In some embodiments, the oxidant is2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

In certain embodiments, the reaction conditions of step (d) comprise anadditive selected from the group consisting of carbonate base (such aspotassium carbonate, potassium bicarbonate, sodium carbonate, or sodiumbicarbonate), amine (such as triethylamine or diisopropylethylamine),acid (organic acids and inorganic acids), and acetate salts (such assodium acetate or potassium acetate). In some embodiments, the additiveis acetic acid.

In certain embodiments, the reaction conditions of step (d) comprise2-methyltetrahydrofuran, or a mixture of toluene and tetrahydrofuran. Incertain embodiments, the reaction conditions of step (d) comprise atemperature of from about −15° C. to about 80° C. or from about −15° C.to about 10° C. In some embodiments, the temperature is about 0° C.

In certain embodiments, the reaction conditions of step (e) comprise adeprotection reagent, wherein the deprotection reagent may behydrochloric acid (including wherein hydrochloric acid is generated fromacetyl chloride), phosphoric acid, trifluoroacetic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonicacid, thionyl chloride, and trimethylsilyl chloride. A wide range ofsolvents may be employed, including but not limited to water, methanol,ethanol, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, andtoluene. Deprotection may proceed at temperatures ranging from about 20°C. to about 110° C. or from about 55° C. to about 65° C.

In certain embodiments, step (e) further comprises neutralizing thecompound of formula (E). In some embodiments, neutralizing the compoundof formula (E) may be in a variety of organic solvents and aqueoussolvents and may be performed at a temperature of from about −20° C. toabout 60° C. or from about 5° C. to about 15° C. The neutralizationreagent may be a wide variety of bases. In certain embodiments, the basemay be sodium methoxide. In some embodiments, the neutralization solventmay be methanol.

In certain embodiments, step (e) further comprises crystallizing thecompound of formula (E). In some embodiments, recrystallization ofcompound formula (E) comprises water, an alcohol (such as 1-propanol,2-propanol, methanol, or ethanol), or acetonitrile. In some embodiments,the temperature may range from about −20° C. to about 100° C. Thetemperature may be from about 60° C. and may be ramped to cool to about20° C. In some embodiments, recrystallization of compound of formula (E)comprises a crystallization reagent. The crystallization reagent may bean acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid,ethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid,oxalic acid, glucuronic acid, or phosphoric acid. In some embodiments,the crystallization reagent is phosphoric acid.

In certain embodiments, the reaction conditions of step (f) comprise asolvent selected from the group consisting of dichloromethane, methanol,N,N-dimethylformamide, and a mixture thereof. In certain embodiments,the reaction conditions of step (f) comprise a temperature of from about−20° C. to about 30° C. or from about 10° C. to about 20° C.

In some embodiments, the reaction conditions of step (f) comprises acoupling agent and an organic base. The coupling agent may be thosetypically known in the art. In some embodiments, the coupling agent is4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. Insome embodiments, the organic base may be an amine. In certainembodiments, the organic base is N-methylmorpholine.

In another embodiment, provided is a process for preparing compound offormula (A):

or a salt or solvate thereof, comprising the steps of:

(a) contacting a compound of formula (I-a), stereoisomer thereof, ormixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G′),stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G′) with a compound of formula(H) or salt thereof:

under conditions sufficient to yield a compound of formula (B),stereoisomer thereof, or mixture of stereoisomers thereof:

(c) cyclizing the compound of formula (B) under conditions sufficient toyield a compound of formula (C):

(d) oxidizing the compound of formula (C) under conditions sufficient toyield a compound of formula (D):

(e) deprotecting the compound of formula (D) under conditions sufficientto yield a compound of formula (E) or a salt thereof:

and

(f) contacting the compound of formula (E) with a compound of formula(F):

under conditions sufficient to yield a compound of formula (A), whereinPG is an amine protecting group.

In certain embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of dichloromethane,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,dimethylformamide, acetone, MEK, and MIBK. In certain embodiments, thereaction conditions of step (a) comprise a temperature of from about 10°C. to about 60° C. or from about 10° C. to about 30° C.

In some embodiments, the reaction conditions of step (a) comprise aphosphate salt or a carbonate salt. In certain embodiments, thephosphate salt includes but is not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄,and Na₃PO₄. In some embodiments, the carbonate salt includes but is notlimited to Na₂CO₃, Cs₂CO₃, and NaHCO₃.

In certain embodiments, the compound of formula (J) is a potassium, asodium, or a cesium salt.

In certain embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, dichloromethane, toluene, isopropyl acetate,ethyl acetate, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, acetone,MEK, MIBK, and a mixture thereof. In certain embodiments, the reactionconditions of step (b) comprise a temperature of from about 40° C. toabout 60° C. or from about 40° C. to about 50° C.

In some embodiments, the reaction conditions of step (b) comprise aphosphate salt or carbonate salt. In certain embodiments, the phosphatesalt includes but is not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄, and Na₃PO₄.In some embodiments, the carbonate salt includes but is not limited toNa₂CO₃, Cs₂CO₃, Li₂CO₃, and NaHCO₃.

In certain embodiments, the compound of formula (H) is a potassium, asodium, or a cesium salt.

In some embodiments, the reaction conditions of step (c) comprise anamine reagent, wherein the amine reagent comprises ammonium acetate,hexamethyldisilzane, ammonia, ammonium formate, ammonium propionate,ammonium hexanoate, or ammonium octanoate.

In certain embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of toluene, xylene, analcohol, and a mixture thereof. In certain embodiments, the reactionconditions of step (c) comprise a temperature of from about 60° C. toabout 110° C. or from about 85° C. to about 95° C. In some embodiments,the alcohol can be isopropanol, 1-propanol, 1-butanol, 2-butanol,2-methoxyethanol, or a glycol, such as ethylene glycol or propyleneglycol. In some embodiments, the reaction condition comprises a mixtureof toluene and isopropanol.

In certain embodiments, the reaction conditions of step (d) comprise anoxidant. In some embodiments, the oxidant is2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

In certain embodiments, the reaction conditions of step (d) comprise anadditive selected from the group consisting of carbonate base (such aspotassium carbonate, potassium bicarbonate, sodium carbonate, or sodiumbicarbonate), amine (such as triethylamine or diisopropylethylamine),acid (organic acids and inorganic acids), and acetate salts (such assodium acetate or potassium acetate). In some embodiments, the additiveis acetic acid.

In certain embodiments, the reaction conditions of step (d) comprise2-methyltetrahydrofuran, or a mixture of toluene and tetrahydrofuran. Incertain embodiments, the reaction conditions of step (d) comprise atemperature of from about −15° C. to about 80° C. or from about −15° C.to about 10° C. In some embodiments, the temperature is about 0° C.

In certain embodiments, the reaction conditions of step (e) comprise adeprotection reagent, wherein the deprotection reagent may behydrochloric acid (including wherein hydrochloric acid is generated fromacetyl chloride), phosphoric acid, trifluoroacetic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonicacid, thionyl chloride, and trimethylsilyl chloride. A wide range ofsolvents may be employed, including but not limited to water, methanol,ethanol, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, andtoluene. Deprotection may proceed at temperatures ranging from about 20°C. to about 110° C. or from about 55° C. to about 65° C.

In certain embodiments, step (e) further comprises neutralizing thecompound of formula (E). In some embodiments, neutralizing the compoundof formula (E) may be in a variety of organic solvents and aqueoussolvents and may be performed at a temperature of from about −20° C. toabout 60° C. or from about 5° C. to about 15° C. The neutralizationreagent may be a wide variety of bases. In certain embodiments, the basemay be sodium methoxide. In some embodiments, the neutralization solventmay be methanol.

In certain embodiments, step (e) further comprises crystallizing thecompound of formula (E). In some embodiments, recrystallization ofcompound formula (E) comprises water, an alcohol (such as 1-propanol,2-propanol, methanol, or ethanol), or acetonitrile. In some embodiments,the temperature may range from about −20° C. to about 100° C. Thetemperature may be from about 60° C. and may be ramped to cool to about20° C. In some embodiments, recrystallization of compound formula (E)comprises a crystallization reagent. The crystallization reagent may bean acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid,ethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid,oxalic acid, glucuronic acid, or phosphoric acid. In some embodiments,the crystallization reagent is phosphoric acid.

In certain embodiments, the reaction conditions of step (f) comprise asolvent selected from the group consisting of dichloromethane, methanol,N,N-dimethylformamide, and a mixture thereof. In certain embodiments,the reaction conditions of step (f) comprise a temperature of from about−20° C. to about 30° C. or from about 10° C. to about 20° C.

In some embodiments, the reaction conditions of step (f) comprises acoupling agent and an organic base. The coupling agent may be thosetypically known in the art. In some embodiments, the coupling agent is4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. Insome embodiments, the organic base may be an amine. In certainembodiments, the organic base is N-methylmorpholine.

In an embodiment, the compound of formula (D):

is prepared by

(a) contacting a compound of formula (I), stereoisomer thereof, ormixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G),stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G) with a compound of formula(H) or salt thereof:

under conditions sufficient to yield a compound of formula (B),stereoisomer thereof, or mixture of stereoisomers thereof:

(c) cyclizing a compound of formula (B) under conditions sufficient toyield a compound of formula (C):

and

(d) dehydrogenating a compound of formula (C) under conditionssufficient to yield a compound of formula (D),

wherein PG is an amine protecting group, X and Y are each independentlyselected from the group consisting of halo, —OSO₂R, —OP(O)OR, and—OP(O)(OR)₂, wherein R is alkyl, haloalkyl, or aryl or substituted aryl.

In some embodiments, the substituted aryl may be an aryl having one ormore substituents, such as alkyl, alkoxy, hydroxyl, nitro, halogen, andothers as discussed above.

In an embodiment, X is bromo and Y is bromo.

In certain embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of dichloromethane,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,dimethylformamide, acetone, MEK, and MIBK. In certain embodiments, thereaction conditions of step (a) comprise a temperature of from about 10°C. to about 60° C. or from about 10° C. to about 30° C.

In some embodiments, the reaction conditions of step (a) comprise aphosphate salt or carbonate salt. In certain embodiments, the phosphatesalt includes but is not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄, and Na₃PO₄.In some embodiments, the carbonate salt includes but is not limited toNa₂CO₃, Cs₂CO₃, and NaHCO₃.

In certain embodiments, the compound of formula (J) is a potassium, asodium, or a cesium salt.

In certain embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, dichloromethane, toluene, isopropyl acetate,ethyl acetate, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, acetone,MEK, MIBK, and a mixture thereof. In certain embodiments, the reactionconditions of step (b) comprise a temperature of from about 40° C. toabout 60° C. or from about 40° C. to about 50° C.

In some embodiments, the reaction conditions of step (b) comprise aphosphate salt or carbonate salt. In certain embodiments, the phosphatesalt includes but is not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄, and Na₃PO₄.In some embodiments, the carbonate salt includes but is not limited toNa₂CO₃, Cs₂CO₃, Li₂CO₃, and NaHCO₃.

In certain embodiments, the compound of formula (H) is a potassium, asodium, or a cesium salt.

In some embodiments, the reaction conditions of step (c) comprises anamine reagent, wherein the amine reagent comprises ammonium acetate,hexamethyldisilzane, ammonia, ammonium formate, ammonium propionate,ammonium hexanoate, or ammonium octanoate.

In certain embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of toluene, xylene, analcohol, and a mixture thereof. In certain embodiments, the reactionconditions of step (c) comprise a temperature of from about 60° C. toabout 110° C. or from about 85° C. to about 95° C. In some embodiments,the alcohol can be isopropanol, 1-propanol, 1-butanol, 2-butanol,2-methoxyethanol, or a glycol, such as ethylene glycol or propyleneglycol. In some embodiments, the reaction condition comprises a mixtureof toluene and isopropanol.

In certain embodiments, the reaction conditions of step (d) comprise anoxidant. In some embodiments, the oxidant is2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

In certain embodiments, the reaction conditions of step (d) comprise anadditive selected from the group consisting of carbonate base (such aspotassium carbonate, potassium bicarbonate, sodium carbonate, or sodiumbicarbonate), amine (such as triethylamine or diisopropylethylamine),acid (organic acids and inorganic acids), and acetate salts (such assodium acetate or potassium acetate). In some embodiments, the additiveis acetic acid.

In certain embodiments, the reaction conditions of step (d) comprise2-methyltetrahydrofuran, or mixture of toluene and tetrahydrofuran. Incertain embodiments, the reaction conditions of step (d) comprise atemperature of from about −15° C. to about 80° C. or from about −15° C.to about 10° C. In some embodiments, the temperature is about 0° C.

In one embodiment, provided is a process for preparing a compound offormula (C):

comprising

(a) contacting a compound of formula (I), stereoisomer thereof, ormixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G),stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G) with a compound of formula(H) or salt thereof:

under conditions sufficient to yield a compound of formula (B),stereoisomer thereof, or mixture of stereoisomers thereof:

and

(c) cyclizing a compound of formula (B) under conditions sufficient toyield a compound of formula (C),

wherein PG is an amine protecting group, X and Y are each independentlyselected from the group consisting of halo, —OSO₂R, —OP(O)OR, and—OP(O)(OR)₂, wherein R is alkyl, haloalkyl, or aryl or substituted aryl.

In some embodiments, the substituted aryl may be an aryl having one ormore substituents, such as alkyl, alkoxy, hydroxyl, nitro, halogen, andothers as discussed above.

In an embodiment, X is bromo and Y is bromo.

In certain embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of dichloromethane,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,dimethylformamide, acetone, MEK, and MIBK. In certain embodiments, thereaction conditions of step (a) comprise a temperature of from about 10°C. to about 60° C. or from about 10° C. to about 30° C.

In some embodiments, the reaction conditions of step (a) comprise aphosphate salt or carbonate salt. In certain embodiments, the phosphatesalt includes but is not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄, and Na₃PO₄.In some embodiments, the carbonate salt includes but is not limited toNa₂CO₃, Cs₂CO₃, and NaHCO₃.

In certain embodiments, the compound of formula (J) is a potassium, asodium, or a cesium salt.

In certain embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, dichloromethane, toluene, isopropyl acetate,ethyl acetate, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, acetone,MEK, MIBK, and a mixture thereof. In certain embodiments, the reactionconditions of step (b) comprise a temperature of from about 40° C. toabout 60° C. or from about 40° C. to about 50° C.

In some embodiments, the reaction conditions of step (b) comprise aphosphate salt or carbonate salt. In certain embodiments, the phosphatesalt includes but is not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄, and Na₃PO₄.In some embodiments, the carbonate salt includes but is not limited toNa₂CO₃, Cs₂CO₃, Li₂CO₃, and NaHCO₃.

In certain embodiments, the compound of formula (H) is a potassium, asodium, or a cesium salt.

In some embodiments, the reaction conditions of step (c) comprises anamine reagent, wherein the amine reagent comprises ammonium acetate,hexamethyldisilzane, ammonia, ammonium formate, ammonium propionate,ammonium hexanoate, or ammonium octanoate.

In certain embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of toluene, xylene, analcohol, and a mixture thereof. In certain embodiments, the reactionconditions of step (c) comprise a temperature of from about 60° C. toabout 110° C. or from about 85° C. to about 95° C. In some embodiments,the alcohol can be isopropanol, 1-propanol, 1-butanol, 2-butanol,2-methoxyethanol, or a glycol, such as ethylene glycol or propyleneglycol. In some embodiments, the reaction condition comprises a mixtureof toluene and isopropanol.

In one embodiment, provided is a process for preparing a compound offormula (I-a), stereoisomer thereof, or mixture of stereoisomersthereof:

comprising the steps of:

(a) cyclizing a compound of formula (L):

under conditions sufficient to yield a compound of formula (K):

and

(b) brominating the compound of formula (K) under conditions sufficientto yield a compound of formula (I-a),

wherein Z is hydrogen, halo, OSO₂R¹, —BF₃ ⁻, —B(OR²)₂, —CO₂H, or —NR¹ ₃wherein R¹ is alkyl, haloalkyl, aryl or substituted aryl, and R² isalkyl. In some embodiments, the substituted aryl may be an aryl havingone or more substituents, such as alkyl, alkoxy, hydroxyl, nitro,halogen, and others as discussed above.

In certain embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of N,N-dimethylacetamide,N,N-dimethylformamide, and acetonitrile. In certain embodiments, thereaction conditions of step (a) comprise a temperature of from about 20°C. to about 80° C. In some embodiments, the temperature is about 80° C.

In certain embodiments, the reaction conditions of step (a) comprise atleast one of palladium catalyst, carbonate salt, and phosphine reagent.In some embodiments, the palladium catalyst may be palladium (II)acetate. In some embodiments, the phosphine reagent may be PPh₃. In someembodiments, the carbonate salt may be potassium carbonate. The reactionconditions may further comprise tetrabutylammonium bromide. The reactionmay take place from about 5 hours to about 7 hours.

In certain embodiments, the reaction conditions of step (b) comprise abrominating reagent selected from the group consisting of pyridiniumtribromide, bromine, and N-bromosuccinimide. In certain embodiments, thereaction conditions of step (b) comprise a solvent selected from thegroup consisting of dichloromethane, methanol, and a mixture thereof. Incertain embodiments, the reaction conditions of step (b) comprise atemperature of about 20° C. The reaction may take place for about 2hours to about 5 hours.

In one embodiment, compound of formula (L) is prepared by contacting acompound of formula (M):

with a compound of formula (N):

under conditions sufficient to yield the compound of formula (L),

wherein X¹ is a leaving group, Y¹ is hydrogen, halo, ortrifluoromethanesulfonate, and Z is hydrogen, halo, —OSO₂R¹, —BF₃ ⁻,—B(OR²)₂, —CO₂H, or —NR¹ ₃ wherein R¹ is alkyl, haloalkyl, aryl orsubstituted aryl, and R² is alkyl. In some embodiments, X¹ is halo, —OH,or —S(O)₂R³, and R³ is alkyl, haloalkyl, or aryl, and the aryl isoptionally substituted with halo, alkyl, haloalkyl, nitro, hydroxyl, oralkoxy.

In certain embodiments, the reaction conditions comprise a solventselected from the group consisting of N,N-dimethylacetamide,tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, andacetonitrile. In certain embodiments, the reaction conditions comprise atemperature of from about 20° C. to about 70° C. In some embodiments,the temperature is about 70° C. In some embodiments, the reactionconditions comprise a carbonate base, such as potassium carbonate.Sodium iodide may also be used. The reaction may take place for about 2hours.

In one embodiment, provided is a process for preparing a compound offormula (I-a):

comprising reacting a compound of formula (O):

under conditions sufficient to yield a compound of formula (I-a).

In certain embodiments, the reaction conditions comprise an oxidizingreagent and palladium catalyst. The palladium catalyst may bedichloro[2-(4,5-dihydro-2-oxazolyl)quinoline]palladium(II). Theoxidizing agent may be tert-butylhydroperoxide. An additive may be used,such as silver tetrafluoroborate.

In some embodiments, the reaction conditions comprise a solvent selectedfrom the group consisting of N,N-dimethylformamide, water, and a mixturethereof. In some embodiments, the reaction conditions comprise atemperature of from about 20° C. to about 25° C. or from about 0° C. toabout 100° C. The reaction may take place for about 30 minutes to about12 hours or from about 30 minutes to about 48 hours.

In one embodiment, a compound of formula (K) is prepared by hydrolyzinga compound of formula (P):

wherein R⁷ is alkyl, under conditions sufficient to yield a compound offormula (K).

In certain embodiments, the reaction conditions comprise an acid. Insome embodiments, the reaction conditions comprise a solvent selectedfrom the group consisting of dichloromethane, water, and a mixturethereof. In some embodiments, the reaction conditions comprise atemperature of from about 5° C. to about 35° C. or from about 0° C. toabout 100° C.

The acid may be trifluoroacetic acid. The reaction may take place fromabout 30 minutes to about 2 hours or from about 30 minutes to about 48hours.

In one embodiment, a compound of formula (K) is prepared by derivatizinga compound of formula (Q):

under conditions sufficient to yield the compound of formula (K).

In certain embodiments, the reaction conditions comprise an acid. Insome embodiments, the reaction conditions comprise a solvent selectedfrom the group consisting of an organic solvent, aqueous solvent, and amixture thereof. In certain embodiments, the reaction conditionscomprise a temperature of from about 0° C. to about 100° C., 60° C. toabout 70° C., or about 65° C. The reaction may take place in about 0.2hours to about 48 hours or for about 3 hours. In some embodiments, thesolvent may be water. In some embodiments, the acid may betrifluoroacetic acid.

In one embodiment, provided is a process for preparing a compound offormula (H):

comprising the steps of:

(a) contacting a salt of a compound of formula (R):

with a compound of formula (S):

under conditions sufficient to yield the compound of formula (T):

and

(b) hydrolyzing the compound of formula (T) under conditions sufficientto yield the compound of formula (H), wherein R⁴ is an optionallysubstituted alkyl or optionally substituted aryl.

In some embodiments, the reaction conditions of step (a) comprise acoupling reagent. In certain embodiments, the reaction conditionscomprise a solvent selected from the group consisting ofN,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone,dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran. Incertain embodiments, the reaction conditions comprise a temperature offrom about 0° C. to about 25° C. In some embodiments, the couplingreagent can be typical peptide coupling reagents, such asN,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate. Insome embodiments, a base, such as diisopropylethylamine, can be used.

In certain embodiments, the reaction conditions of step (b) comprise ahydroxide base. In certain embodiments, the reaction conditions of step(b) comprise a solvent selected from the group consisting oftetrahydrofuran, an alcohol (such as methanol, ethanol, or isopropanol),water, N,N-dimethylformamide, N,N-dimethylacetamide,N-methyl-2-pyrrolidone, and a mixture thereof. In certain embodiments,the reaction conditions of step (b) comprise a temperature of from about15° C. to about 25° C. In some embodiments, the hydroxide base may besodium hydroxide, potassium hydroxide, or lithium hydroxide. In someembodiments, the solvent may be a mixture of tetrahydrofuran, methanol,and water.

In one embodiment, a compound of formula (R) is prepared by (a)cyclizing a compound of formula (U):

under conditions sufficient to yield the compound of formula (V):

and

(b) contacting the compound of formula (V) with an acid under conditionssufficient to yield the complex of formula (R), wherein PG is an amineprotecting group and R⁴ is an optionally substituted alkyl or optionallysubstituted aryl.

In certain embodiments, the reaction conditions of step (a) comprise aborohydride reagent and an organic acid. In certain embodiments, thereaction conditions of step (a) comprise an alkyl acetate solvent. Incertain embodiments, the reaction conditions of step (a) comprise atemperature of from about −10° C. to about 0° C. or about −10° C. toabout 20° C. The alkyl acetate solvent may be, for example, ethylacetate, isopropyl acetate, propyl acetate, butyl acetate, and the like.The borohydride reagent may be sodium triacetoxyborohydride, sodiumborohydrodride, or sodium tripropionoxyborohydride. The organic acid maybe trifluoroacetic acid, acetic acid, or propionic acid. In someembodiments, sodium triacetoxyborohydride and trifluoroacetic acid maybe used.

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of dichloromethane, toluene,ethyl acetate, isopropyl acetate, methanol, ethanol, and isoprophanol.In some embodiments, the reaction conditions of step (b) comprise ethylacetate. In some embodiments, the reaction conditions of step (b)comprise a temperature of from about 15° C. to about 110° C. or about15° C. to about 80° C.

In some embodiments, the acid is selected from the group consisting oftrifluoroacetic acid, hydrochloric acid, methanesulfonic acid,benezensulfonic acid, and napthalenesulfonic acid. In some embodiments,the complex of formula (R) is a trifluoroacetate salt, hydrochloridesalt, mesylate salt, besylate salt, or naphthalenesulfonate salt.

In some embodiments, the acid is para-toluenesulfonic acid, and the saltof formula (R) is a para-toluenesulfonic salt. In such embodiments, R⁴is an ethyl group. In some embodiments, the acid is hydrochloric acid,and the salt of formula (R) is a hydrochloric salt. In such embodiments,the R⁴ can be a benzyl group.

In one embodiment, provided is a process for preparing a complex offormula (R-a):

comprising the steps of:

(a) cyclizing a compound of formula (U′):

under conditions sufficient to yield the compound of formula (V′):

and

(b) contacting the compound of formula (V′) with para-toluenesulfonicacid, wherein PG is an amine protecting group, under conditionssufficient to yield the complex of formula (R-a).

In certain embodiments, the reaction conditions of step (a) comprise aborohydride reagent and an organic acid. In certain embodiments, thereaction conditions of step (a) comprise an alkyl acetate solvent. Incertain embodiments, the reaction conditions of step (a) comprise atemperature of from about −10° C. to about 0° C. or about −10° C. toabout 20° C. The alkyl acetate solvent may be, for example, ethylacetate, isopropyl acetate, N-propyl acetate, butyl acetate, and thelike. The borohydride reagent may be sodium triacetoxyborohydride,sodium borohydrodride, or sodium tripropionoxyborohydride. The organicsolvent may be trifluoroacetic acid, acetic acid, or propionic acid. Insome embodiments, sodium triacetoxyborohydride and trifluoroacetic acidmay be used. In some embodiments, step (a) comprises cyclizing andreducing a compound of formula (U′).

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of dichloromethane, toluene,ethyl acetate, isopropyl acetate, methanol, ethanol, and isoprophanol.In some embodiments, the reaction conditions of step (b) comprise ethylacetate. In some embodiments, the reaction conditions of step (b)comprise a temperature of from about 15° C. to about 110° C. or about15° C. to about 80° C.

In one embodiment, provided is a process for preparing a compound offormula (J) or salt thereof:

comprising the steps of:

(a) contacting a compound of formula (W):

with a hydroboration reagent under conditions sufficient to yield acompound of formula (X):

(b) methylating the compound of formula (X) under conditions sufficientto yield a compound of formula (Y):

and

(c) resolving the compound of formula (Y) under conditions sufficient toyield a compound of formula (J), wherein PG is an amine protecting groupand PG¹ is a carboxylic acid protecting group.

In some embodiments, the reaction conditions of step (a) comprise ahydroboration reagent, wherein the hydroboration reagent isborane-dimethylsulfide. In some embodiments, the reaction conditions ofstep (a) comprise a solvent selected from the group consisting oftetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran,isopropyl acetate, isobutyl acetate, diethyl ether, isopropyl ether,toluene, and N,N-dimethylformamide. In some embodiments, the reactionconditions of step (a) comprise a temperature of from about −30° C. toabout −20° C. or about 0° C. to about 100° C.

In some embodiments, the reaction conditions of step (b) may comprise anacid and methanol. In some embodiments, the acid may be hydrochloricacid. In some embodiments, the reaction conditions of step (a) comprisea temperature of from about 20° C. to about 60° C. or about 25° C.

In an embodiment, a compound of formula (J) or salt thereof is preparedby:

(a) contacting a compound of formula (Z):

with HCN or salt thereof under conditions sufficient to yield a compoundof formula (AA):

(b) contacting the compound of formula (AA) with an acyl halide or acidand R⁶—OH under conditions sufficient to yield a compound of formula(BB):

(c) selective hydrolysis of the compound of formula (BB) underconditions sufficient to form a compound of formula (CC):

(d) contacting the compound of formula (CC) with a borane reagent underconditions sufficient to yield a compound of formula (DD):

and

(e) methylating the compound of formula (DD) under conditions sufficientto yield a compound of formula (J),

wherein R⁵ is a leaving group, R⁶ is an optionally substituted alkyl, PGis an amine protecting group, and PG¹ is a carboxylic acid protectinggroup.

In some embodiments, R⁵ may be halo, —OH, or —OSO₂R⁸, wherein R⁸ isalkyl, haloalkyl, aryl, or substituted aryl. In some embodiments, R⁵ maybe —OTs. In some embodiments, the reaction conditions of step (a)comprise a sodium or potassium salt of HCN. In certain embodiments, thereaction conditions of step (a) comprise a solvent selected from thegroup consisting of dimethylsulfoxide, dimethylformamide, ordimethylacetamide.

In certain embodiments, the reaction conditions of step (b) comprise anacid. In certain embodiments, the reaction conditions of step (b)comprise a solvent selected from the group consisting of methanol,dioxane, chloroform, benzene, and nitrobenzene. In certain embodiments,the reaction conditions of step (b) comprise a temperature of from about20° C. to about 60° C. In some embodiments, the temperature may be about55° C. The acid may be hydrochloric acid, sulfuric acid, methanesulfonicacid, hydrobromic acid, camphorsulfonic acid, para-toluene sulfonicacid, or acetic acid.

In certain embodiments, the reaction conditions of step (b) may furthercomprise an additional step to add a protecting group(s) if necessary(e.g. if protecting groups have been cleaved during the reaction). Suchmethods are well-known in the art and can vary based on the protectiongroup used as described herein. For example, in some embodiments,di-tert-butyl dicarbonate may be used along with sodium bicarbonate andethyl acetate at a temperature of about 20° C.

In certain embodiments, the reaction conditions of step (c) comprise ahydroxide salt. In certain embodiments, the reaction conditions of step(c) comprise a solvent selected from the group consisting oftetrahydrofuran, methanol, and 2-methyltetrahydrofuran. In certainembodiments, the reaction conditions of step (c) comprise a temperatureof from about −20° C. to about 20° C. or about 0° C. The hydroxide saltmay be sodium hydroxide, lithium hydroxide, potassium hydroxide, orbarium hydroxide.

In certain embodiments, the reaction conditions of step (d) comprise asolvent selected from the group consisting of 2-methyltetrahydrofuran,methanol, ethanol, tetrahydrofuran, and water. In certain embodiments,the reaction conditions of step (d) comprise a temperature of from about−20° C. to about 40° C. or about 20° C.

In some embodiments, the borane reagent comprises diborane or a boranecomplex, wherein the borane complex comprises a borane dimethyl sulfidecomplex, borane-tetrahydrofuran complex, or a borane-amine complex.

In some embodiments, the reaction conditions of step (e) comprise methyliodide and a base selected from the group consisting of a hydroxidesalt, 2,6-lutidine, 2,6-di-tert-butyl-methyl pyridine, and potassiumtert-butoxide. In some embodiments, the reaction conditions of step (e)comprise a solvent selected from the group consisting oftetrahydrofuran, dichloromethane, acetonitrile, water, methanol,dimethyl sulfoxide, and toluene. In some embodiments, the reactionconditions of step (e) comprise a temperature of from about −10° C. toabout 40° C. or from about −4° C. to about 1° C. In some embodiments,the base is sodium hydroxide.

The present processes may be prepared using methods disclosed herein androutine modifications thereof which will be apparent given thedisclosure herein and methods well known in the art. Conventional andwell-known synthetic methods may be used in addition to the teachingsherein. The synthesis of typical compounds described herein, e.g.compounds having structures described by one or more of Formula A, B, C,D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z, AA,BB, CC, DD, EE, A-a, A-b, B-a, C-a, D-a, E-a, E-b, G-a, G′, I-a, I-b,J-a, L-a, M-a, M-b, M-c, P-a, R-a, T-a, U-a, U′, V-a, V′, W-a, X-a, Y-a,AA-a, BB-a, BB-b, CC-a, DD-a, DD-b, or other formulas or compoundsdisclosed herein (e.g. numbered compounds 1-1, 1-2, etc.), may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers.

Compounds

In other embodiments, the disclosure provides for intermediate compoundsthat are useful in the processes described herein. Thus, for instance,one embodiment is a compound of the formula (L):

wherein Z is hydrogen, halo, —OSO₂R¹, —BF₃ ⁻, —B(OR²)₂, —CO₂H, or —NR¹ ₃wherein R¹ is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl, and R² is alkyl.

In an embodiment, Z is bromo. In some embodiments, Z is chloro. In someembodiments, the substituted aryl may be an aryl having one or moresubstituents, such as alkyl, alkoxy, hydroxyl, nitro, halogen, andothers as discussed above.

In another embodiment, provided is a compound of formula (Q):

EXAMPLES

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of compounds described herein, may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers. Unless otherwise noted, the starting materials forthe following reactions may be obtained from commercial sources.

Example 1: Synthesis of Compound (H)

Grignard Addition: Conversion of Compound (1-1) to Compound (U-a)

A reaction vessel was charged with THF (30 mL) followed by 3 M MeMgBr inTHF (19.4 ml, 58.4 mmol, 1.5 equiv). The solution was cooled to about−12° C. and then a solution of N-Boc-pyroglutamic acid ethyl ester (10.0g, 38.9 mmol, 1 equiv) (Compound (1-1)) in THF (20 mL) was added intothe reaction contents over 30 minutes maintaining internal temperatureof about less than −5° C. Upon reaction completion, 20% aq NH₄Cl (50 mL)was added and the mixture was phase separated. The aqueous phase wasextracted with EtOAc (50 mL) and the combined organic phases were thenwashed with 1:1 (v/v) 20% aq NH₄Cl/10% aq NaCl (50 mL). The organicphase was polish filtered through a Celite pad and then concentrated byrotary evaporation and further dried to afford Compound (U-a): ¹H NMR(400 MHz, CDCl3) δ 5.24-4.94 (br s, 1H), 4.37-3.95 (m, 3H), 2.70-2.36(m, 2H), 2.30-1.97 (m, 4H), 1.96-1.76 (m, 1H), 1.61-1.38 (m, 9H),1.36-1.05 (m, 3H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of N-Boc-pyroglutamic acidethyl ester, alternative starting material may be N-Boc-pyroglutamicacid benzyl ester, N-Boc-pyroglutamic acid methyl ester,N-Boc-pyroglutamic acid isopropyl ester, N-Boc-pyroglutamic acid t-butylester. Additionally, the Grignard reagent may be methylmagnesiumchloride in lieu of methylmagnesium bromide.

Alternative solvents may be used in the reaction, such astetrahydrofuran, methyl-tetrahydrofuran, t-butylmethyl ether, andcyclopentyl methyl ether. The reaction may also take place intemperatures ranging from about −78° C. to about 10° C. or about −10° C.to about 0° C.

Reductive Cyclization: Conversion of Compound (U-a) to Compound (V-a)

A reaction flask was charged with sodium triacetoxyborohydride (9.7 g,46 mmol, 1.3 equiv) and EtOAc (48 mL). The mixture was cooled to about−10° C. and a solution of Compound (U-a) (9.5 g, 35 mmol, 1 equiv) inEtOAc (48 mL) was added followed by trifluoroacetic acid (11.5 mL, 150mmol, 4.3 equiv) while maintaining content temperature at less than 0°C. Upon reaction completion, 20% aq K₂HPO₄ (25 mL) was added and themixture was phase separated. The organic phase was washed with 20% aqK₂HPO₄ (3×25 mL) followed by H₂O (25 mL) and then concentrated andfurther dried to afford Compound (V-a). ¹H NMR (400 MHz, CDCl3) δ4.46-3.77 (m, 4H), 2.34-1.79 (m, 9H), 1.73-0.98 (m, 10H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, sodiumtristrifluoroacetoxyborohydride or sodium tripropionyloxyborohydride maybe used in lieu of sodium triacetoxyborohydride. Additionally, in lieuof trifluoroacetic acid, acetic acid or prioionic acid may be used.Alternative solvents may include isopropyl acetate, propyl acetate, andbutyl acetate, and temperatures ranging from about −10 to about 0° C. orabout −10 to about 20° C. may be employed.

Deprotection and Salt Formation: Conversion of Compound (V-a) toCompound (R-a)

A reaction flask was charged with para-toluenesulfonic acid monohydrate(6.6 g, 35 mmol, 1 equiv) and then a solution of Compound (V-a) (11.0 g,assumed 35 mmol, 1 equiv) in EtOAc (40 mL) was polish filtered through apad of Celite into the flask followed by a rinse forward of EtOAc (10mL). The mixture was warmed to about 50° C. and held for about 90 min.Upon reaction completion, the slurry was cooled to about 20° C. and thenfiltered, rinsing forward EtOAc (2×10 mL). The solids were dried undervacuum at about 40° C. to afford Compound (R-a). ¹H NMR (400 MHz, CD₃OD)δ 7.70 (d, J=4.6 Hz, 2H), 7.23 (d, J=4.6 Hz, 2H), 4.54-4.40 (m, 1H),4.40-4.18 (m, 2H), 3.88-3.64 (m, 1H), 2.53-2.33 (m, 5H), 2.32-2.08 (m,2H), 1.80-1.56 (m, 1H), 1.43 (d, J=6.6 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of para-toluenesulfonic acid,alternative reagents may be trifluoroacetic acid, anhydrous HCl,hydrochloric acid, methanesulfonic acid, benzenesulfonic acid,naphthalenesulfonic acid. Various solvents may also be used, such asdichloromethane, toluene, isopropyl acetate, methanol, ethanol, andisopropanol. The reaction may be carried out at temperatures of about15° C. to about 110° C. The resultant salt may be isolated as atrifluoroacetate salt, hydrochloride salt, mesylate salt, besylate salt,and naphthalenesulfonate salt.

Peptide Coupling of Compound (R-a) to Form Compound (T-a)

A reaction vessel was charged with Compound (R-a) (30.0 g, 91.0 mmol, 1equiv), 2-(S)-methoxycarbonylamino-3-methyl-butyric acid (17.5 g, 100mmol, 1.10 equiv), and HATU (38.0 g, 100 mmol, 1.10 equiv) followed bydichloromethane (450 mL) and diisopropylethylamine (49.6 mL, 300 mmol,3.30 equiv). After about 1 h, the mixture was concentrated by rotaryevaporation and diluted with ethyl acetate (200 mL). The solution waswashed with 10% HCl (4×50 mL) followed by 5% Na₂CO₃ (4×50 mL) and 20%NaCl (50 mL). The organic phase was filtered through Celite,concentrated, and then evaporated from dichloromethane to produce crudeCompound (T-a) that was used without further purification.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative reagents may be T3P,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, CDI,EDCI-HOBt, EDCI-HATU, isobutyl chloroformate/NMM. The reaction may takeplace in various solvents, including DMAc, NMP, DCM, THF, 2-Me-THF, andin temperatures of about 0° C. to about 25° C.

Ester Hydrolysis of Compound (T-a) to Form Compound (H)

Crude Compound (T-a) was added with THF (200 mL) and MeOH (50 mL) toproduce a solution. To this solution was added a solution of LiOH (10.9g, 0.455 mol) in water (100 mL). After about 13 h, the reaction wasconcentrated by rotary evaporation and the resulting solution was washedwith MTBE (3×50 mL). The aqueous phase was polish filtered throughCelite and acidified to pH 2 with 6N HCl (100 mL). The mixture wasextracted with dichloromethane (3×50 mL) and the combined organic phaseswere dried over Na₂SO₄, filtered and concentrated to produce Compound(H). ¹H NMR (400 MHz, d₆-acetone) δ 6.50-6.19 (m, 1H), 4.80-4.53 (m,1H), 4.48-4.29 (m, 1H), 4.27-3.94 (m, 1H), 3.75-3.38 (m, 3H), 2.44-1.52(m, 9H), 1.32 (d, 3H), 0.96 (m, 6H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, various bases may be used, such assodium hydroxide and potassium hydroxide. Various solvents, such asethanol, isopropanol, DMF, DMAc, and NMP, may be used and temperaturesmay range from about 15° C. to about 25° C.

Example 2: Synthesis of Compound (J-a)

Hydrolysis and Boc-Protection: Conversion of Compound (AA-a) to Compound(BB-a)

Acetyl chloride (9.88 kg, 126 mol) was added slowly to cold methanol(6.73 kg). The resulting methanolic hydrogen chloride solution was addedover about 1 hour to a solution of Compound (AA-a) (4.26 kg, 16.8 mol)in methanol (10.1 kg) while maintaining reaction temperature below 25°C. The reaction mixture was agitated at about 20° C. for about 1 hour,and then heated at reflux until reaction completion. The reactionmixture was concentrated under vacuum, cooled to about 15° C., andbasified with sodium bicarbonate (8 wt. % aqueous solution, 34.9 L).Ethyl acetate (19.2 kg) and a solution of di-tert-butyl dicarbonate(3.66 kg, 16.8 mol) in ethyl acetate (7.7 kg) were added, the mixturewas agitated for about 1 hour, and the layers were separated. Theaqueous layer was extracted with ethyl acetate (12.8 kg) and thecombined organic layers were concentrated under vacuum to provideCompound (BB-a). ¹H NMR (400 MHz, CDCl₃) δ: 4.25 (dt, 1H), 3.84-3.52(comp m, 8H), 3.01 (m, 1H), 2.45 (m, 1H), 2.28 (m, 1H), 1.38 (m, 9H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, various acids may be employed forhydrolysis, such as sulfuric acid, methanesulfonic acid, hydrobromicacid, camphorsulfonic acid, para-toluene sulfonic acid, and acetic acid,and alternative solvents may include dioxane, chloroform, benzene, andnitrobenzene. Alternatively, hydrolysis may be carried out withpalladium in methanol. The reaction may take place at temperatures ofabout 20° C. to about 60° C.

Other boc-protection reagents, including but not limited to phenyltert-butyl carbonate, tert-butyl N-succinimidyl carbonate, tert-butyl4-formylphenyl carbonate, and tert-butyl carbonate azide, may be used.Alternative bases for use during the boc-protection step may includephosphate bases (such as potassium phosphate monobasic, potassiumphosphate dibasic, potassium phosphate tribasic, sodium phosphatemonobasic, sodium phosphate dibasic, and sodium phosphate tribasic),carbonate bases (such as potassium carbonate and cesium carbonate),hydroxide bases (such as potassium hydroxide, sodium hydroxide, lithiumhydroxide), hydrides (such as sodium hydride), and organic bases (suchas amines, including triethyl amine, diisopropyl amine, and diisopropylethyl amine). Various solvents, such as methyl tert-butyl ether,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, isobutylacetate, methyl acetate, diethyl ether, isopropyl ether,dichloromethane, toluene, and N,N-dimethylformamide, may be employed.Temperatures may also range from about 0° C. to about 100° C.

Selective Ester Hydrolysis to Prepare Compound (CC-a)

Sodium hydroxide (1 N aqueous solution, 20.2 kg, 20.2 mol) was addedover about 2 hours to a solution of Compound (BB-a) (4.32 kg, 15.04 mol)in tetrahydrofuran (22 kg) while maintaining reaction temperature below−1° C. Upon complete conversion, glacial acetic acid (0.5 kg) was addedand the mixture was warmed to about 20° C. Methyl tert-butyl ether (13.6kg) was added, the mixture was agitated, and the layers were separated.The organic layer was extracted twice with sodium bicarbonate (5%aqueous solution, 2×8.5 kg). The three aqueous layers were combined,methyl tert-butyl ether (14.5 kg) was added, and the mixture wasacidified to pH 1 with hydrochloric acid (10% aqueous solution, 14.7 kg)while maintaining internal temperature below 15° C. The layers wereseparated and the aqueous layer was extracted with methyl tert-butylether (13.7 kg). The combined organic layers were washed twice with 25%brine (2×8.2 kg), and concentrated under vacuum to the minimum stirrablevolume. 2-Methyltetrahydrofuran (28 kg) was charged to the residue andthe mixture was concentrated under vacuum to the minimum stirrablevolume. 2-Methyltetrahydrofuran (19.6 kg) was charged to the residue toprovide Compound (CC-a) as a solution. ¹H-NMR (400 MHz, acetone-d6) δ:4.27 (t, 1H), 3.83-3.52 (comp m, 5H), 3.19 (m, 1H), 2.55 (m, 1H), 2.19(m, 1H), 1.39 (m, 9H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative bases may include lithiumhydroxide, potassium hydroxide, barium hydroxide, and enzymes. Varioussolvents, such as methanol or Me-THF, may be employed, and temperaturesmay range from −20° C. to 20° C.

Reduction of Compound (CC-a) to Form Compound (DD-a)

Borane-dimethyl sulfide complex (2 M solution in tetrahydrofuran, 9.2kg, 1.5 equiv.) was added over 90 minutes to a solution of Compound(CC-a) (3.8 kg) in 2-methyltetrahydrofuran (16.5 kg), while maintainingreaction temperature below 25° C. Upon complete conversion 10% aqueousammonium acetate solution (19.6 kg) was added, the mixture was agitatedfor about 1 hour, and the layers were separated. The organic layer wasdiluted with methyl tert-butyl ether (7.2 kg) and washed with 10%aqueous ammonium acetate solution (11.4 kg). The combined aqueous layerswere back-extracted with methyl tert-butyl ether (6.8 kg). The combinedorganic layers were washed with 20% brine solution (12.7 kg) andconcentrated under vacuum to provide Compound (DD-a). ¹H NMR (400 MHz,CDCl₃) δ: 4.28 (dt, 1H), 3.73 (s, 3H), 3.65 (m, 3H), 3.25 (dd, 1H), 2.42(m, 2H), 1.79 (m, 1H), 1.63 (s, 1H), 1.44 (m, 9H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, other reduction reagents may be used.Non-limiting examples include sodium borohydride-boron trifluorideetherate mixture, diborane, borane-tetrahydrofuran complex, and variousborane-amine complexes (such as borane-triethylamine,borane-diethylaniline and the like). Alternatively, activation reagentsmay also be used, and non-limiting examples of such activation reagentsinclude thionyl chloride, oxalyl chloride, 1,1′-carbonyldiimidazole,2-chloro-4,6-dimethoxy-1,3,5-triazine, cyanuric chloride,N,N′-dicyclohexylcarbodiimide, ethyl chloroformate, isobutylchloroformate, N-hydroxysuccinimide, and 2,2,2-trifluoroethanol;reduction reagents may then include sodium sodium borohydride andlithium borohydride. Various solvents, such as methanol, ethanol,tetrahydrofuran, and water, may be used, and temperatures can range fromabout −20° C. to 40° C.

Synthesis of Compound (3-2) from Compound (DD-a)

An aqueous solution of sodium hydroxide (30% w/w, 103 g) is added to asolution of Compound (DD-a) (80.3 g) in methyl tert-butyl ether (320 mL)at about 10° C. The mixture is warmed to about 20° C. and agitated forabout 2 hours. Water (80 mL) is added, the mixture is agitated, and thenthe layers are separated. Sodium chloride (20.8 g) is charged to theaqueous layer and agitated until dissolved. The solution is cooled toabout 5° C. and then an aqueous solution of 15% w/w hydrochloric acid(195 g) is added over about 2 hours. The batch is seeded with Compound(3-2) (0.08 g) and the contents are agitated for about 1 hour. Theresulting slurry is filtered and the isolated solids are washed with anaqueous solution of 10% w/w sodium chloride (240 mL) followed by water(40 mL). The wet solids are dried to provide Compound (3-2).

Synthesis of Compound (J-a) from Compound (3-2)

Methyl iodide (18.3 mL) is added to a solution of Compound (3-2) (48.0g) in tetrahydrofuran (240 mL) and the mixture is cooled to about 10° C.Sodium tert-butoxide (45.0 g) is added over about 10 minutes and thenthe reaction mixture is warmed to about 20° C. and agitated for about anadditional 3 hours. Methyl tert-butyl ether (125 mL) and water (125 mL)are then added. The biphasic mixture is agitated, the layers areseparated, and the organic layer is extracted with water (125 mL). Theaqueous layers are combined and sodium chloride (48.0 g) is added.Methyl tert-butyl ether (192 mL) is added and the temperature isadjusted to about 10° C. A solution of 15% w/w hydrochloric acid (60 g)is added over about 15 minutes. The mixture is agitated and the layersare separated. The organic layer is washed sequentially with a solutionof 20% w/w sodium metabisulfite/10% w/w sodium chloride (48 mL) followedby 10% w/w sodium chloride (48 mL), then dried over magnesium sulfateand filtered. One third of the total organic filtrate was concentratedto remove the solvent and then isopropanol (38 mL) is added. Thesolution is concentrated to remove solvent and then isopropanol (7.5 mL)is added. The solution is adjusted to about 20° C. and water (12 mL) isadded. The solution is seeded with Compound (J-a) (0.04 g) and agitatedfor about 30 minutes. Water (3 mL) is added and the mixture is agitatedfor about 1 hour. Water (33 mL) is added over about 2 hours and then themixture is heated to about 35° C. over about 1.5 hours. The mixture isagitated at about 35° C. for about 2 hours and then cooled to about 0°C. over about 3.5 hours. The resulting slurry is filtered, washed with amixture of 5:1 v/v water:isopropanol (7.5 mL), and dried to provideCompound (J-a). ¹H NMR (400 MHz, acetone-d6) δ: 4.20 (dd, 1H), 3.61 (m,1H), 3.35 (m, 2H), 3.26 (s, 3H), 3.10 (m, 1H), 2.45 (m, 2H), 1.73 (m,1H), 1.39 (m, 9H).

Alternative Synthesis of Compound (J-a) from Compound (DD-a)

Methyl iodide (11.8 kg) was added to a solution of Compound (DD-a) (3.0kg, 11.5 mol) in tetrahydrofuran (20 kg). Sodium hydroxide (20 wt. %aqueous solution, 9.3 kg) was added over about 1 hour while maintainingreaction temperature below about 15° C., and the mixture was dilutedwith methyl tert-butyl ether (8.8 kg) and water (3 kg). The mixture wasagitated, the layers were separated, and the organic layer was extractedwith water (6.2 kg). The combined aqueous layers were acidified to pH 1with hydrochloric acid (10 wt. % aqueous solution, 34.0 kg) andextracted twice with methyl tert-butyl ether (2×9.7 kg). The combinedorganic layers were washed with sodium bisulfite (10 wt. % aqueoussolution, 6 kg) and 10% brine (6 kg), and concentrated under vacuum.Toluene (18.6 kg) was added, and the solution was concentrated undervacuum. The residue was dissolved in toluene (5.4 kg), heptane (3.0 kg)was added, and the batch was seeded with Compound (J-a) (0.034 kg).Heptane (12.8 kg) was added over 30 minutes, and the resulting slurrywas stirred at about 20° C. for about 2 hours. The precipitated productwas filtered, washed with heptane (4.2 kg), and dried under vacuum atabout 20° C. to provide Compound (J-a).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, other reagents and additives mayinclude dimethyl sulfate, methyl p-toluenesulfonate, methyl triflate,and methyl carbonate. Silver triflate may also be added. Various bases,such as potassium hydroxide, 2,6-lutidine, 2,6-di-tert-butyl-methylpyridine, and potassium tert-butoxide, sodium tert-butoxide, lithiumhydroxide, may also be employed. Alternative solvents include but arenot limited to dichloromethane, acetonitrile, tetrahydrofuran, water,methanol, dimethyl sulfoxide, and toluene. The reaction may also proceedat temperatures ranging from about 0° C. to about 60° C. or about 15° C.Compound (J-a) may also be isolated in various forms, such as adicyclohexylamine salt in toluene, isopropyl acetate, methyl tert-butylether, and 2-methyltetrahydrofuran; a dicyclohexylamine salt in toluene,isopropyl acetate, methyl tert-butyl ether, and 2-methyltetrahydrofuran;a sodium salt; potassium salt; or lithium salt.

Example 3: Alternative Synthesis of Compound (J-a)

Esterification of Compound (3-1) to Form Compound (W-a)

A reactor is charged with Compound (3-1) (100 g, 0.440 mol, 1.0 equiv),4,4-dimethylamino-pyridine (10.7 g, 0.088 mol, 0.2 equiv) and methyltert-butyl ether (600 mL). To this solution is added di-tert-butyldicarbonate (105 g, 0.484 mol, 1.1 equiv) over 2 hours. The resultingmixture is stirred at about 20° C. to about 30° C. for additional about2 to about 3 hours until the reaction is complete and then washedsuccessively with dilute hydrochloric acid (200 mL), dilute aqueoussodium hydroxide solution (200 mL) and brine (100 mL). The organic phaseobtained after layer separation is dried over anhydrous sodium sulfateand concentrated by vacuum distillation to obtain Compound (W-a), whichis used directly in the next step.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, other boc-protection reagents,including but not limited to phenyl tert-butyl carbonate, tert-butylN-succinimidyl carbonate, tert-butyl 4-formylphenyl carbonate, andtert-butyl carbonate azide, may be used. Various solvents, such asmethyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran,isopropyl acetate, isobutyl acetate, methyl acetate, diethyl ether,isopropyl ether, dichloromethane, toluene, and N,N-dimethylformamide,may be employed. Temperatures may also range from about 0° C. to about100° C.

Synthesis of Compound (X-a) from Compound (W-a)

(−)-Pinene (28.0 g, 205.6 mmol, 3 equiv) is added slowly to 100 mL of1.0 M borane-dimethylsulfide (100 mmol, 1.5 equiv) solution intetrahydrofuran while maintaining reaction temperature below about −20°C. The resulting mixture is warmed slowly to about 25° C. over about 2.5hours and stirred for additional 2 hours. The mixture is then cooled toabout −30° C. and a solution of 18.8 g of crude Compound (W-a) (66.4mmol) in 18.8 mL of tetrahydrofuran is added slowly while maintainreaction temperature below about −20° C. The reaction mixture is thenwarmed to about 0° C. over 1 hour and stirred at this temperature forabout 15 hours. Water is added slowly until gas evolution subsides, andthen the reaction mixture is diluted with 40 mL of Na₂PO₄/NaOH solution(10 g dibasic sodium phosphate and 1 g sodium hydroxide dissolved in 40mL of water). 35 mL of 30% hydrogen peroxide solution is added whilemaintaining reaction temperature below about 5° C. The reaction mixtureis then warmed to about 25° C. and stirred at this temperature foradditional 1 hour. Layers are separated and the aqueous layer isextracted with methyl tert-butyl ether (90 mL). The combined organicphase is washed successively with 20% aqueous sodium sulfite solution(100 mL) and brine (90 mL), dried over anhydrous sodium sulfate. Thefiltrate is concentrated under vacuum to obtain crude Compound (X-a),which is used directly in the next step.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, additional hydroborating reagents,including but not limited to borane-THF complex, borane-amine complex,disiamylborane, monoisopinocamphenylborane, diethylborane,dimesitylborane and 9-BBN, may be used. Various solvents, such as methyltert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, isopropylacetate, isobutyl acetate, diethyl ether, isopropyl ether, toluene, andN,N-dimethylformamide may be employed. Temperatures may also range fromabout 0° C. to about 100° C.

Deprotection of Compound (X-a) to Form Compound (3-2)

Compound (X-a) (48 g) is mixed with 20% methanolic HCl (90 mL) andagitated at about 25° C. for about 15 hours. The mixture is thenconcentrated by vacuum distillation, mixed with methanol (50 mL), andconcentrated again. The residue is mixed with water (100 mL) and methyltert-butyl ether (50 mL). Layers are separated, and the organic phase isextracted with water (50 mL). The combined aqueous phase is treated with15% aqueous sodium hydroxide to adjust pH to about 7-8. To this mixtureis charged di-tert-butyl dicarbonate (21.7 g, 99.4 mmol, 1.5 equiv)followed by 15% aqueous sodium hydroxide (35.0 g). The mixture isagitated at about 25° C. for 3 hours, and then methyl tert-butyl ether(30 mL) is charged. The layers are separated and sodium chloride (30 g)is charged to the aqueous layer. The aqueous layer is treated with 10%aqueous hydrochloric acid to adjust to pH 2-3 and then extracted twicewith ethyl acetate (100 mL and 50 mL). The organic layers are combined,and concentrated to dryness by vacuum distillation. The residue isredissolved in methyl-tert-butyl ether (30 mL) and then concentratedagain. This operation is repeated twice to complete solvent replacementfrom ethyl acetate to methyl tert-butyl ether. The final solution inabout 30 mL of methyl tert-butyl ether is stirred at ambient temperaturefor about 1 hour to obtain a slurry. The solids are isolated byfiltration and dried to provide crude Compound (3-2).

Crude Compound (3-2) (11 g) is dissolved at about 45° C. in a mixture ofmethyl tert-butyl ether (30 mL) and methanol (10 mL). The solution isconcentrated and solvent exchanged into methyl tert-butyl ether to causeprecipitation of the product. The precipitated product is isolated btfiltration and dried to obtain purified Compound (3-2).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, various acids may be employed forhydrolysis, such as sulfuric acid, methanesulfonic acid, hydrobromicacid, camphorsulfonic acid, para-toluene sulfonic acid, and acetic acid,and alternative solvents may include dioxane, chloroform, benzene, andnitrobenzene. Alternatively, hydrolysis may be carried out withpalladium in methanol. The reaction may take place at temperatures ofabout 20° C. to about 60° C.

Other boc-protection reagents, including but not limited to phenyltert-butyl carbonate, tert-butyl N-succinimidyl carbonate, tert-butyl4-formylphenyl carbonate, and tert-butyl carbonate azide, also may beused. Alternative bases for use during the boc-protection step mayinclude phosphate bases (such as potassium phosphate monobasic,potassium phosphate dibasic, potassium phosphate tribasic, sodiumphosphate monobasic, sodium phosphate dibasic, and sodium phosphatetribasic), carbonate bases (such as potassium carbonate and cesiumcarbonate), hydroxide bases (such as potassium hydroxide, sodiumhydroxide, lithium hydroxide), hydrides (such as sodium hydride), andorganic bases (such as amines, including triethyl amine, diisopropylamine, and diisopropyl ethyl amine).

Various solvents, such as methyl tert-butyl ether,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, isobutylacetate, methyl acetate, diethyl ether, isopropyl ether,dichloromethane, toluene, and N,N-dimethylformamide, may be employed.Temperatures may also range from about 0° C. to about 100° C.

Methylation of Compound (3-2) to Form Compound (Y-a)

Compound (3-2) (7.0 g, 28.5 mmol) is dissolved in tetrahydrofuran (35mL). The resulting solution is mixed with 50% aqueous sodium hydroxide(13.7 g, 171.3 mmol, 6.0 equiv) and then with methyl iodide (12.2 g,86.0 mmol, 3.0 equiv). The mixture is agitated at about 25° C. for about15 hours and then concentrated by vacuum distillation to remove most ofthe organic solvent. The concentrate is diluted with methyl tert-butylether (50 mL) and water (50 mL) and treated with 10% aqueoushydrochloric acid to adjust pH to 2-3. Layers are separated, the aqueouslayer is extracted with methyl tert-butyl ether (25 mL). The organiclayers are combined and then washed with brine (25 mL), and dried overanhydrous sodium sulfate. The filtered solution is concentrated byvacuum distillation to obtain crude Compound (Y-a).

To a solution of 15.2 g crude Compound (Y-a) (58.6 mmol, 1.0 equiv) inmethyl tert-butyl ether (120 mL) is added dicyclohexylamine (9.0 g, 46.9mmol, 0.85 equiv). The mixture is warmed to about 60° C. and agitatedfor about 3 hours. The resulting slurry is cooled slowly to about 20° C.over 2 hours, and then agitated for an additional 2 hours. The slurry isfiltered and the filter cake rinsed with methyl tert-butyl ether (30 mL)to provide Compound (Y-a) as a dicyclohexylamine salt, which is a whitesolid.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, other reagents and additives mayinclude dimethyl sulfate, methyl p-toluenesulfonate, methyl triflate,and methyl carbonate. Silver triflate may also be added. Various bases,such as potassium hydroxide, 2,6-lutidine, 2,6-di-tert-butyl-methylpyridine, and potassium tert-butoxide, sodium tert-butoxide, lithiumhydroxide, may also be employed. Alternative solvents include but arenot limited to dichloromethane, acetonitrile, tetrahydrofuran, water,methanol, dimethyl sulfoxide, and toluene. The reaction may also proceedat temperatures ranging from about 0° C. to about 60° C. or about 15° C.Compound (Y-a) may also be isolated in various forms, such as a sodiumsalt, potassium salt, or lithium salt.

Synthesis of Compound (J-a) from Compound (Y-a)

The dicyclohexylamine salt of Compound (Y-a) (14.6 g) is mixed withmethyl tert-butyl ether (75 mL) and water (75 mL) and the pH adjusted to10-11 with 15% aqueous sodium hydroxide. Layers are separated, and theorganic phase is discarded. To the aqueous phase is added methyltert-butyl ether (75 mL) and then the pH is adjusted to 2-3 by additionof 10% hydrochloric acid while maintaining temperature below 25° C.Layers are separated, and the aqueous phase is extracted with methyltert-butyl ether (37.5 mL). The combined organic phase is washed withbrine (37.5 mL) and then dried with anhydrous sodium sulfate. Themixture is filtered and the filtrate is concentrated to dryness byvacuum distillation. The residue is mixed with hexane (30 mL) and theresulting mixture is concentrated to dryness by vacuum distillation. Theresidue is mixed with hexane (75 mL) and dichloromethane (3.75 mL). Themixture is heated to about 60° C. and agitated for about 1 hour. Themixture is then cooled slowly to about 20° C. over about 2 hours andagitated for an additional 1 hour. The precipitated solids are isolatedby filtration, rinsed with hexane (30 mL) and dried to obtain Compound(J-a).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative bases for use during saltbreak may include other hydroxide bases (such as potassium hydroxide andlithium hydroxide), phosphate bases (such as potassium phosphatetribasic, potassium phosphate dibasic, sodium phosphate dibasic, andsodium phosphate tribasic), and carbonate bases (such as potassiumcarbonate, sodium carbonate and cesium carbonate). Various solvents,such as methyl tert-butyl ether, 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, isobutyl acetate, methyl acetate,diethyl ether, isopropyl ether, dichloromethane, and toluene may beemployed.

Example 4: Alternative Synthesis of Compound (J-a)

Cyclization of Compound (4-1) to form Compound (4-2)

A mixture of tetrahydrofuran (152 kg, 171 L) and sodium formate (29.8kg, 425 mol, 3.8 equiv) is cooled to about 0° C. to about 5° C. andagitated for about 1 hour. To this mixture is slowly charged acetylchloride (26.7 kg, 340 mol, 3.0 equiv) while maintaining the internaltemperature at about 0° C. to about 5° C. The mixture is agitated forabout 30 minutes, then warmed to about 25° C. and agitated for anadditional 14 to 16 hours until the reaction is complete.

A second reactor is charged with tetrahydrofuran (323 kg, 363 L) andlithium amide (12.5 kg, 544 mol, 4.8 equiv). The mixture is heated toabout 50° C. to about 60° C. and hexamethyldisilazane (96.9 kg, 600 mol,5.3 equiv) is added over 3 to 4 hours. The mixture is agitated for anadditional 1 to 2 hours, adjusted to about 65° C. to about 75° C., andagitated for 10 to 15 hours. The resulting solution of lithiumhexamethyldisilazide is cooled to about −75° C. to −70° C. A solution ofCompound (4-1) (36 kg, 113 mol) in tetrahydrofuran (93 L) is added over1 to 2 hours while maintaining the internal temperature at about −75° C.to −70° C. The solution of acetic formic anhydride is then added to thecold reaction mixture. The resulting reaction mixture is warmed slowlyto about −65° C. to about −60° C. over 1 to 2 hours, and then a solutionacetic acid (55 kg, 52 L, 916 mol, 8.1 equiv) in tetrahydrofuran (55 kg,62 L) is charged while maintaining the internal temperature below about−35° C. The temperature of the reaction mixture is adjusted to about−20° C. to about −10° C., and water (183 L) is charged while maintainingthe internal temperature below about 10° C. The layers are separated andthe aqueous layer is extracted with methyl tert-butyl ether (183 kg, 247L). The organic layers are combined and washed with brine (209 kg, 175L), followed by water (190 L). The layers are separated and the organiclayer is dried with anhydrous sodium sulfate (30 kg) for 1 hour. Theslurry is filtered and the filter is rinsed with dichloromethane (60 kg,45 L). The filtrate is concentrated by vacuum distillation at 40-50° C.The reactor is charged with dichloromethane (100 kg, 75 L) and themixture is concentrated by vacuum distillation at 40-50° C. A secondportion of dichloromethane (100 kg, 75 L) is charged and the mixture isconcentrated by vacuum distillation at 40-50° C. The residue isdissolved in dichloromethane (256 kg, 192 L), cooled to about 0° C. toabout 5° C. and trifluoroacetic acid (12.9 kg, 8.7 L, 113 mol, 1 equiv)is added to the mixture while maintaining the internal temperature below5° C. The mixture is agitated for about 30 minutes, then warmed to about20° C. to about 25° C. and agitated for an additional 6 to 10 hours. Theinternal temperature is adjusted to 10° C. to about 20° C. and 10%aqueous sodium carbonate (150 kg, 142 mol, 1.3 equiv) is slowly chargedto adjust to pH 6 to 7. The mixture is adjusted to about 30° C. to about40° C. and distilled under vacuum to remove approximately 160 kgdichloromethane (120 L). The mixture is then adjusted to about 20° C. toabout 35° C. and extracted with methyl tert-butyl ether (180 kg, 243 L).The layers are separated and the aqueous layer is extracted with asecond portion of methyl tert-butyl ether (180 kg, 243 L). The organiclayers are combined and washed with 10% aqueous sodium chloride solution(120 kg, 112 L). The layers are separated and the organic layer is driedwith anhydrous sodium sulfate (50 kg). The slurry is passed throughsilica gel (15 kg), eluting with methyl tert-butyl ether (60 kg, 81 L).The eluent is concentrated to an oil by vacuum distillation at about 35°C. to about 45° C. and the residue is dissolved in methanol (40 kg, 51L) and used directly in the next step.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative bases may include, butare not limited to, lithium diisopropylamide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and thelike. Alternative formylation agents, in lieu of acetic formicanhydride, may be phenyl formate, 2,2,2-trifluoroethyl formate, and thelike. Various solvents may be used, including but not limited tomethyltetrahydrofuran, cyclopentyl methyl ether, and the like.

Hydrogenation of Compound (4-2) to Form Compound (BB-b)

The solution of Compound (4-2) in methanol is charged into ahydrogenation reactor and mixed with 10% palladium on carbon (4.5 kg,4.2 mol, 0.04 equiv), methanol (120 kg, 152 L), and acetic acid (0.9 kg,15.0 mol, 0.1 equiv). The reactor is pressurized with hydrogen gas andthe mixture is agitated at about 20° C. to about 30° C. until thereaction is deemed complete by TLC analysis (e.g. for about 12 to 16hours). The mixture is then filtered to remove solids and the filtrateis concentrated by vacuum distillation at 30° C. to about 40° C. toobtain crude Compound (BB-b). The residue is dissolved intetrahydrofuran (30 kg, 34 L) and used directly in the next step.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, other catalysts, such as platinumdioxide, palladium acetate and charcoal mixture,bis(triphenylphosphine)ruthenium(II)dichloride, and the like, may beemployed. Alternative reducing agents may be ammonium formate, formicacid, triethylsilane, and the like. Alternative solvents, include butare not limited to, ethanol, ethyl acetate, isopropyl acetate,methyltetrahydrofuran, tetrahydrofuran, and water. The reaction may alsoproceed at temperatures ranging from about 0° C. to about 60° C.

Reduction of Compound (BB-b) to Form Compound (X-a)

Crude Compound (BB-b) is mixed with tetrahydrofuran (90 kg, 101 L) andwater (30 L). The temperature of the mixture is adjusted to about 20° C.to about 25° C., and sodium borohydride (14.4 kg, 381 mol, 4.0 equiv) isadded. The resulting mixture is agitated at about 20 to about 25° C.until the reaction is deemed complete by TLC analysis (e.g. for about 2to 4 hours). The mixture is then cooled to about 0° C. to about 10° C.,and 12% aqueous hydrochloric acid (30 kg, 28 L) is charged to adjust pHto 6-7. The mixture is filtered through Celite (10 kg) and the filter isrinsed with methyl tert-butyl ether (30 kg, 41 L). The filtrate isallowed to settle to allow layer separation. Layers are separated andthe aqueous layer is extracted twice with methyl tert-butyl ether (150kg, 203 L). The organic layers are combined and washed with brine (50kg, 42 L) and concentrated by vacuum distillation at about 35° C. toabout 45° C. to an oil. To the residue is mixed with methanol (60 kg, 76L), and the resulting solution is concentrated by vacuum distillation atabout 35-45° C. to obtain crude Compound (X-a) which is used directly inthe next step.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, other reduction reagents may be used.Non-limiting examples include lithium borohydride, lithium aluminumhydride, diborane, 9-BBN, borane-tetrahydrofuran complex, and the like.Various solvents, such as methanol, ethanol, methyltetrahydrofuran,monoglyme, diglyme, and the like, may be used. The reaction may alsotake place at temperatures that range from about −20° C. to about 40° C.

Syntheses of Compound (I-a)

The synthesis of Compound (I-a) from Compound (X-a) can be carried outas described in Example 3.

Example 5: Synthesis of Compound (I-a)

Alkylation of Compound (5-1) with Compound (N) to Compound (5-2)

To a mixture of 7-hydroxy-3,4-dihydronaphthalen-1(2H)-one (Compound (N))(1.0 g) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (1.75 g) (Compound(5-1)) and N,N-dimethylacetamide (5 mL) at ambient temperature was addedpotassium carbonate (1.28 g). After complete conversion, the mixture wasdiluted with water (10 mL) and the mixture was filtered. The filter cakewas washed with water and the isolated solids dried under reducedpressure at 50° C. to afford7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (Compound(5-2)). HRMS (ESI⁺ MS/MS) Calculated for C₁₇H₁₅BrClO₂ m/z (M+H):364.9944, and 366.9923. Found: 364.9947, and 366.9948. ¹H NMR (400 MHz,CDCl₃) δ 7.62 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J=8.5 Hz, 1H),7.24-7.11 (m, 3H), 5.10 (s, 2H), 2.98-2.86 (m, 2H), 2.70-2.60 (m, 2H),2.21-2.06 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative electrophiles include1-bromo-4-chloro-2-(chloromethyl)benzene,1-bromo-4-chloro-2-(fluoromethyl)benzene,1-bromo-4-chloro-2-(iodomethyl)benzene, 2-bromo-5-chlorobenzyl4-methylbenzenesulfonate, 2-bromo-5-chlorobenzyl benzenesulfonate,(2-bromo-5-chlorophenyl)methanol, 2-bromo-5-chlorobenzylmethanesulfonate, 2-bromo-5-chlorobenzyl trifluoromethanesulfonate, and2-bromo-5-chlorobenzyl 4-nitrobenzenesulfonate.

Additionally, a variety of bases may be used, including lithiumcarbonate, sodium carbonate, cesium carbonate, beryllium carbonate,magnesium carbonate, calcium carbonate, strontium carbonate, bariumcarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide,cesium hydroxide, beryllium hydroxide, magnesium hydroxide, calciumhydroxide, strontium hydroxide, barium hydroxide, lithium bicarbonate,sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, berylliumbicarbonate, magnesium bicarbonate, calcium bicarbonate, strontiumbicarbonate, barium bicarbonate, lithium hydride, sodium hydride,potassium hydride, magnesium hydride, calcium hydride, lithiumtert-butoxide, sodium tert-butoxide, potassium tert-butoxide, cesiumtert-butoxide, beryllium tert-butoxide, magnesium tert-butoxide, calciumtert-butoxide, strontium tert-butoxide, barium tert-butoxide, aluminumtert-butoxide, titanium tert-butoxide, 2,2,6,6-tetramethylpiperidine,2,6-ditertbutylpyridine, 4-methyl-2,6-ditertbutylpyridine, trilithiumphosphate, trisodium phosphate, tripotassium phosphate, tricesiumphosphate, beryllium phosphate, magnesium phosphate, calcium phosphate,strontium phosphate, dilithium hydrogenphosphate, disodiumhydorgenphosphate, dipotassium hydrogenphosphate, dicesiumhydrogenphosphate, lithium dihydrogenphosphate, sodiumdihydrogenphosphate, potassium dihydrogenphosphate, and cesiumdihydrogenphosphate.

Various solvents may be employed. Non-limiting examples may beN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrolidine,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,diethylether, acetone, methylethyl ketone, methylisobutylketone,diisopropyl ether, 1,4-dioxane, 1,2-dimethoxyethane, chloroform,acetonitrile, toluene, dichloromethane, and nitromethane.

The reaction may take place at temperatures that range from about 35° C.or about 0° C. to about 40° C. and at time lengths of about 1 hour toabout 48 hours or about 24 hours.

Cyclization of Compound (5-2) to Compound (5-3)

A mixture of7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (1.00 g)(Compound (5-2)), potassium carbonate (1.19 g), triphenylphosphine (38.3mg), palladium (II) acetate (32.4 mg), pivalic acid (86.4 mg) andN,N-dimethylacetamide (5 mL) was heated to about 60° C. After completeconsumption of the starting material, water (20 mL) was added. Themixture was filtered, and the filter cake washed with water (2×20 mL)and then with hexane (2×5 mL). The filter cake was dried under reducedpressure at ambient temperature to provide3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (Compound(5-3)). ¹H NMR (400 MHz, CDCl₃) δ 77.65 (d, J=8.3 Hz, 1H), 7.61 (s, 1H),7.54 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 5.06 (s, 2H),3.02-2.86 (m, 2H), 2.73-2.53 (m, 2H), 2.26-2.00 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative cyclization startingmaterial in lieu of7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one caninclude 7-(2,5-dichlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one,7-(5-chloro-2-iodobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one,4-chloro-2-((8-oxo-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)phenyltrifluoromethanesulfonate,7-(5-bromo-2-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one,7-(2,5-dibromobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one,7-(5-bromo-2-iodobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one, and4-bromo-2-((8-oxo-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)phenyltrifluoromethanesulfonate. Other starting materials can include Compound(5-6):

wherein X may be —Cl, —Br, —I, —OH, R^(b)CO₂—, R^(b)SO₂—, and HSO₂—. Ymay be —Cl, —Br, —I, —OH, R^(b)CO₂—, R^(b)SO₂—, and HSO₂—. R^(b) may beDO—, MeO—, EtO—, PrO—, iPrO— BuO—, PhO—, toluyl-O—, 4-NO₂PhO—, CF₃CH₂O—,CF₃O—, CF₂HO—, CFHO—, alkoxy, and Aryl-O—.

The metal component of the catalyst can vary. Non-limiting examplesinclude palladium(II) trifluoroacetate, palladium(II) acetylacetonate,allylpalladium(II) chloride dimer, palladium (II) acetate, palladium(II) pivalate, palladium (II) chloride, palladium (II) bromide,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium,bis(acetonitrile)dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct,tetrakis(triphenylphosphine)palladium(0),dichlorobis(tricyclohexylphosphine)palladium(II),bis(triphenylphosphine)palladium(II) dichloride,dichlorobis(tri-o-tolylphosphine)palladium(II),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane,[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II),tetrakis(acetonitrile)palladium(II) tetrafluoroborate, (SPhos)palladium(II) phenethylamine chloride, (XPhos) palladium(II)phenethylamine chloride, (RuPhos) palladium(II) phenethylamine chloride,(t-BuXPhos) palladium(II) phenethylamine chloride, and (BrettPhos)palladium(II) phenethylamine chloride.

The ligand component of the catalyst may be any ligands known in theart. For example, the ligand component may be tri-tert-butylphosphine,tri-tert-butylphosphine hydro tetrafluoroborate,methyl-di-tert-butylphosphine, methyl-di-tert-butylphosphine hydrotetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,tri(p-tolyl)phosphine, tri-(2-furyl)phosphine,4-(dimethylamino)phenyldiphenylphosphine, tri(4-fluorophenyl)phosphine,tri(4-trifluoromethylphenyl)phosphine, tri(4-methoxyphenyl)phosphine,tri(3-methylphenyl)phosphine, tri(2-methylphenyl)phosphine,tri(cyclohexyl)phosphine, Tri(2-furanyl)phosphine,1,1′-bis(diphenylphosphino) ferrocene, 1,1′-bis(dicyclohexylphosphino)ferrocene, 1,1′-bis(ditertbutylphosphino) ferrocene,1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride,1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride,1,3-diisopropylimidazolium tetrafluoroborate,1,3-bis(1-adamantyl)imidazolium tetrafluoroborate,2-(dicyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,2-dicyclohexylphosphino-2′-methylbiphenyl,2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl,2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonatehydrate, 2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl,(2-biphenyl)di-tert-butylphosphine,2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-di-tert-butylphosphino-2′-methylbiphenyl,2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl,2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,and the like.

Alternative acids and bases may be employed. Examples of acids may bepropanoic acid, butyric acid, pentanoic acid, isobutyric acid,tert-butylcarboxylic acid, adamantylcarboxylic acid, and trifluoroaceticacid. Examples of bases may be lithium carbonate, sodium carbonate,cesium carbonate, beryllium carbonate, magnesium carbonate, calciumcarbonate, strontium carbonate, barium carbonate, lithium hydroxide,sodium hydroxide, potassium hydroxide, cesium hydroxide, berylliumhydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide,barium hydroxide, lithium bicarbonate, sodium bicarbonate, potassiumbicarbonate, cesium bicarbonate, beryllium bicarbonate, magnesiumbicarbonate, calcium bicarbonate, strontium bicarbonate, bariumbicarbonate, lithium hydride, sodium hydride, potassium hydride,magnesium hydride, calcium hydride, lithium tert-butoxide, sodiumtert-butoxide, potassium tert-butoxide, cesium tert-butoxide, berylliumtert-butoxide, magnesium tert-butoxide, calcium tert-butoxide, strontiumtert-butoxide, barium tert-butoxide, aluminum tert-butoxide, titaniumtert-butoxide, 2,2,6,6-tetramethylpiperidine, 2,6-ditertbutylpyridine,4-methyl-2,6-ditertbutylpyridine, trilithium phosphate, trisodiumphosphate, tripotassium phosphate, tricesium phosphate, berylliumphosphate, magnesium phosphate, calcium phosphate, strontium phosphate,dilithium hydrogenphosphate, disodium hydrogenphosphate, dipotassiumhydrogenphosphate, dicesium hydrogenphosphate, lithiumdihydrogenphosphate, sodium dihydrogenphosphate, potassiumdihydrogenphosphate, cesium dihydrogenphosphate, lithiumtert-butylcarboxylate, sodium tert-butylcarboxylate, potassiumtert-butylcarboxylate, cesium tert-butylcarboxylate, lithium acetate,sodium acetate, potassium acetate, cesium acetate, lithium propanoate,sodium propanoate, potassium propanoate, cesium propanoate, lithiumisobutyrate, sodium isobutyrate, potassium isobutyrate, cesiumisobutyrate, lithium adamantylcarboxylate, sodium adamantylcarboxylate,potassium adamantylcarboxylate, cesium adamantylcarboxylate, lithiumtrifluoroaceate, sodium trifluoroaceate, potassium trifluoroaceate, andcesium trifluoroaceate.

Exemplary solvents can include N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrolidine, 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, acetone, methylethylketone, methylisobutylketone, diisopropyl ether, 1,4-dioxane,1,2-dimethoxyethane, chloroform, acetonitrile, toluene, dichloromethane,dimethylsulfoxide, and diisopropylether.

Alternative palladium scavengers may be employed, such as N-acetylcysteine, activated charcoal, charcoal, ethylenediaminetetraacetic acid,1,2-ethylenediamine, 1,2-diaminopropane, diethylenetriamine,triethylenetetramine, and tris(2-aminoethyl)amine.

The reaction can take place at temperatures ranging from about 60° C. toabout 70° C. or about 20° C. to about 100° C., and at time length ofabout 5 hours to 6 hours of about 1 hour to about 48 hours.

Suzuki Reaction of Compound (5-3) to Compound (O)

3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (5.00 g)(Compound (5-3)) was combined with palladium (II) acetate (0.20 g),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.72 g)2-methyltetrahydrofuran (50 mL). A solution of potassium hydroxide (3.94g) and water (29 mL) was added followed by potassiumvinyltrifluoroborate (3.53 g). The mixture was heated to about 70° C.After complete conversion, the temperature was adjusted to about 50° C.and N-acetyl cysteine (0.72 g) was added followed by celite (2.5 g).After 3 h, the mixture was filtered and the organic phase was washedwith a 5% aqueous potassium hydroxide solution (15 mL) and 1M aqueoushydrochloric acid (1×75 mL and 1×50 mL). The organic phase wasconcentrated under reduced pressure and the temperature adjusted toabout 50° C. Heptane (10 mL) was added, the temperature adjusted toabout 23° C. and the mixture was filtered. The filter cake was washedwith heptane (5 mL) and dried under reduced pressure at about 40° C. toprovide 3-vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (Compound(O)). HRMS (ESI⁺ MS/MS) Calculated for C₁₉H₁₇O₂ m/z (M+H): 277.1229;Found: 277.1238; ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J=8.0 Hz, 1H), 7.62(s, 1H), 7.58 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 6.72 (dd,J=17.5, 10.9 Hz, 1H), 5.81 (d, J=17.6 Hz, 1H), 5.32 (d, J=10.8 Hz, 1H),5.11 (s, 2H), 3.03-2.89 (m, 2H), 2.70-2.58 (m, 2H), 2.21-2.06 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative starting materials mayinclude 3-bromo-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-iodo-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yltrifluoromethanesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl benzenesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl4-methylbenzenesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl4-fluorobenzenesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl4-(trifluoromethyl)benzenesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylic acid,lithium8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, sodium8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,potassium8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, cesium8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, methyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, ethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, propyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,isopropyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, butyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,isobutyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,2,2,2-trifluoroethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, phenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,p-tolyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,4-nitrophenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,4-fluorophenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,4-(trifluoromethyl)phenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,4-methoxyphenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,trifluoromethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,difluoromethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, andfluoromethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate.Additional alternative starting material can include Compound (5-7),Compound (5-8), Compound (5-8), and Compound (5-10):

wherein R^(c) may be alkoxy, aryloxy, heteroaryloxy, and X may be halo,—OSO₂R^(h), and wherein R^(h) may be alkyl, haloalkyl, aryl orsubstituted aryl. In some embodiments, the substituted aryl may be anaryl having one or more substituents, such as alkyl, alkoxy, hydroxyl,nitro, halogen, and others as discussed above.

Alternative vinyl components may also be employed. Non-limiting examplesof such components can include compounds of the following structures:

wherein R^(e) can include alkyl or ethylene, R^(f) can include alkyl oraryl, and metal may be zinc (e.g. when used in combination with Compound(5-7) or Compound (5-10)), magnesium, lithium, or aluminum.

Additional examples of the vinyl components can be vinylboronic acid,dimethyl vinylboronate, diethyl vinylboronate, dipropyl vinylboronate,diisopropyl vinylboronate, dibutyl vinylboronate,4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane,4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane,6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione, vinylboronicanhydride pyridine complex, (+)-vinylboronic acid pinanediol ester,6-[(1R,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-2-Vinyl-1,3,6,2-dioxazaborocane-4,8-dione,vinyltrimethylsilane, vinyltriethylsilane, dimethyldivinylsilane,tetravinylsilane, chloro(dimethyl)vinylsilane, trichlorovinylsilane,vinyltrimethoxysilane, triisopropoxy(vinyl)silane, triethoxyvinylsilane,tris(trimethylsiloxy)(vinyl)silane, triacetoxy(vinyl)silane,tris(allyloxy)(vinyl)silane, vinyltriisopropenoxysilane,tris(2-methoxyethoxy)(vinyl)silane,1,3,5,7,9,11,13,15-octavinylpentacyclo[9.5.1.1˜3,9˜.1˜5,15˜.1˜7,13˜]octasiloxan,triphenoxy(vinyl)silane,1,3,5,7,9,11,13-heptaisobutyl-15-vinylpentacyclo[9.5.1.1˜3,9˜.1˜5,15˜.1˜7,13˜]octasiloxane,1-vinyl-2,8,9-trioxa-5-aza-1-silabicyclo[3.3.3]undecane, vinylzincChloride, vinylzinc bromide, vinyl lithium, vinyl magnesium chloride,vinyl magnesium bromide, and vinyl aluminum.

Any metal components and ligand components of the catalyst known in theart can also be employed. Metal components can include palladium(II)trifluoroacetate, palladium(II) acetylacetonate, allylpalladium(II)chloride dimer, palladium(II) acetate, palladium(II) pivalate,palladium(II) chloride, palladium(II) bromide,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium,bis(acetonitrile)dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct,tetrakis(triphenylphosphine)palladium(0),dichlorobis(tricyclohexylphosphine)palladium(II),bis(triphenylphosphine)palladium(II) dichloride,dichlorobis(tri-o-tolylphosphine)palladium(II),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane,[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II),tetrakis(acetonitrile)palladium(II) tetrafluoroborate, (SPhos)palladium(II) phenethylamine chloride, (XPhos) palladium(II)phenethylamine chloride, (RuPhos) palladium(II) phenethylamine chloride,(t-BuXPhos) palladium(II) phenethylamine chloride, and (BrettPhos)palladium(II) phenethylamine chloride.

Non-limiting examples of ligand components may betri-(2-furyl)phosphine, tri-tert-butylphosphine, tri-tert-butylphosphinehydro tetrafluoroborate, methyl-di-tert-butylphosphine,methyl-di-tert-butylphosphine hydro tetrafluoroborate,4,5-bis(dicyclohexylphosphino)-9,9-dimethylxanthene,tri(cyclohexyl)phosphine, tri(2-furanyl)phosphine,1,1′-bis(diphenylphosphino) ferrocene, 1,1′-bis(dicyclohexylphosphino)ferrocene, 1,1′-bis(ditertbutylphosphino) ferrocene,1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride,1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride,1,3-diisopropylimidazolium tetrafluoroborate,1,3-bis(1-adamantyl)imidazolium tetrafluoroborate,2-(dicyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′-methylbiphenyl,2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl,2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonatehydrate, 2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl,(2-biphenyl)di-tert-butylphosphine,2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-di-tert-butylphosphino-2′-methylbiphenyl,2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl,2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,and the like.

Various bases may also be employed. Non-limiting examples may be lithiumcarbonate, sodium carbonate, cesium carbonate, beryllium carbonate,magnesium carbonate, calcium carbonate, strontium carbonate, bariumcarbonate, lithium hydroxide, sodium hydroxide potassium hydroxide,cesium hydroxide, beryllium hydroxide, magnesium hydroxide, calciumhydroxide, strontium hydroxide, barium hydroxide, lithium bicarbonate,sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, berylliumbicarbonate, magnesium bicarbonate, calcium bicarbonate, strontiumbicarbonate, barium bicarbonate, lithium hydride, sodium hydride,potassium hydride, magnesium hydride, calcium hydride, lithiumtert-butoxide, sodium tert-butoxide, potassium tert-butoxide, cesiumtert-butoxide, beryllium tert-butoxide, magnesium tert-butoxide, calciumtert-butoxide, strontium tert-butoxide, barium tert-butoxide, aluminumtert-butoxide, titanium tert-butoxide, 2,2,6,6-tetramethylpiperidine,2,6-ditertbutylpyridine, 4-methyl-2,6-ditertbutylpyridine, trilithiumphosphate, trisodium phosphate, tripotassium phosphate, tricesiumphosphate, beryllium phosphate, magnesium phosphate, calcium phosphate,strontium phosphate, dilithium hydrogenphosphate, disodiumhydrogenphosphate, dipotassium hydrogenphosphate, dicesiumhydrogenphosphate, lithium dihydrogenphosphate, sodiumdihydrogenphosphate, potassium dihydrogenphosphate, cesiumdihydrogenphosphate, lithium tert-butylcarboxylate, sodiumtert-butylcarboxylate, potassium tert-butylcarboxylate, cesiumtert-butylcarboxylate, lithium acetate, sodium acetate, potassiumacetate, cesium acetate, lithium propanoate, sodium propanoate,potassium propanoate, cesium propanoate, lithium isobutyrate, sodiumisobutyrate, potassium isobutyrate, cesium isobutyrate, lithiumadamantylcarboxylate, sodium adamantylcarboxylate, potassiumadamantylcarboxylate, cesium adamantylcarboxylate, lithiumtrifluoroaceate, sodium trifluoroaceate, potassium trifluoroaceate,cesium trifluoroaceate, triethylamine, trimethylamine, tripropylamine,tributylamine, diisopropylethylamine, dicyclohexylmethylamine, lithiummethoxide, lithium ethoxide, lithium isopropoxide, lithium propoxide,lithium butoxide, lithium phenoxide, sodium methoxide, sodium ethoxide,sodium isopropoxide, sodium butoxide, sodium phenoxide, potassiummethoxide, potassium ethoxide, potassium isopropoxide, potassiumpropoxide, potassium butoxide, potassium phenoxide, cesium methoxide,cesium ethoxide, cesium isopropoxide, cesium propoxide, cesium butoxide,and cesium phenoxide.

Alternative solvents can be N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrolidine, 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, diisopropylether,acetone, methylethyl ketone, methylisobutylketone, diisopropyl ether,1,4-dioxane, 1,2-dimethoxyethane, chloroform, acetonitrile, toluene,dichloromethane, 1,2-dichloroethane, dimethylsulfoxide, methanol,ethanol, n-propanol, 2-propanol, butanol, tert-butanol, benzene, andnitromethane.

Various additives may be employed, such as butylated hydroxytoluene,ascorbic acid, sodium ascorbate. Alternative palladium scavengers may beN-acetyl cysteine, activated charcoal, charcoal,ethylenediaminetetraacetic acid, 1,2-ethylenediamine,1,2-diaminopropane, diethylenetriamine, triethylenetetramine, andtris(2-aminoethyl)amine.

The reaction may take place at temperatures ranging from about 70° C. orabout 20° C. to about 100° C., and the reaction may take place in about2 hours to about 6 hours or about 1 hour to about 48 hours.

Reaction of Compound (O) to Compound (5-4)

3-Vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (30 g) (Compound(O)) was combined with dichloromethane (60 mL), dimethylsulfoxide (150mL) and water (11 mL) and cooled to about 15° C. N-Bromosuccinimide(21.3 g) was added in portions. After complete conversion,dichloromethane was added (135 mL). The mixture was washed with a 13%aqueous sodium thiosulfate solution (135 mL) followed by addition ofdichloromethane (225 mL). The organic phase was washed with water (120mL) and then concentrated under reduced pressure. Methylcyclohexane wasadded. The mixture was cooled to about 5° C. and filtered. The filtercake was washed with methylcyclohexane (100 mL) and then dried underreduced pressure at about 40° C. to provide3-(2-bromo-1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (5-4)). HRMS (ESI⁺ MS/MS) Calculated for C₁₉H₁₈BrO₃ m/z (M+H):373.0439, and 375.0419; Found: 373.0450, and 375.0432; ¹H NMR (400 MHz,CDCl₃) δ 7.74 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.41 (d,J=7.9 Hz, 1H), 7.23 (s, 1H), 5.11 (s, 2H), 5.03-4.85 (m, 1H), 3.74-3.62(m, 1H), 3.60-3.46 (m, 1H), 3.05-2.86 (m, 2H), 2.75 (s, 1H), 2.68-2.56(m, 2H), 2.23-2.06 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, various brominating agents may beemployed, such as bromine, bromine monochloride,5,5-dimethyl-1,3-dibromohydantoin, pyridinium tribromide,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric Acid,tribromoisocyanuric Acid, N-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N′-dibromo-4-methylbenzenesulphonamide, sodium bromate, lithiumbromate, potassium bromate, tetra-n-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, N-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin,3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione,dibromo(triphenyl)phosphorane, carbon tetrabromide, bromoform,dibromomethane, hexabromoacetone, lithium bromide, sodium bromide,potassium bromide, cesium bromide, beryllium bromide, magnesium bromide,calcium bromide, aluminum bromide, indium bromide, titanium bromide,ferrous bromide, ferric bromide, tin bromide, and hydrobromic acid.

Alternative oxygenating agents may be employed. Non-limiting examplesmay include lithium carbonate, sodium carbonate, potassium carbonate,cesium carbonate, beryllium carbonate, magnesium carbonate, calciumcarbonate, cerium carbonate, lithium bicarbonate, sodium bicarbonate,potassium bicarbonate, cesium bicarbonate, beryllium bicarbonate,magnesium bicarbonate, calcium bicarbonate, barium bicarbonate, lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,beryllium hydroxide, magnesium hydroxide, calcium hydroxide, strontiumhydroxide, barium hydroxide, formic acid, lithium formate, sodiumformate, potassium formate, cesium formate, beryllium formate, magnesiumformate, calcium formate, tert-butylcarboxylic acid, lithiumtert-butylcarboxylate, sodium tert-butylcarboxylate, potassiumtert-butylcarboxylate, cesium tert-tutylcarboxylate, acetic acid,lithium acetate, sodium acetate, potassium acetate, cesium acetate,propanoic acid, lithium propanoate, sodium propanoate, potassiumpropanoate, cesium propanoate, butyric acid, lithium butyrate, sodiumbutyrate, potassium butyrate, cesium butyrate, beryllium butyrate,magnesium butyrate, calcium butyrate, barium butyrate, isobutyric acid,lithium isobutyrate, sodium isobutyrate, potassium isobutyrate, cesiumisobutyrate, adamantylcarboxylic acid, lithium adamantylcarboxylate,sodium adamantylcarboxylate, potassium adamantylcarboxylate, cesiumadamantylcarboxylate, lithium trifluoroaceate, sodium trifluoroaceate,potassium trifluoroaceate, cesium trifluoroaceate, benzoic acid, lithiumbenzoate, sodium benzoate, potassium benzoate, cesium benzoate,beryllium benzoate, magnesium benzoate, calcium benzoate, 4-nitrobenzoicacid, lithium 4-nitrobenzoate, sodium 4-nitrobenzoate, potassium4-nitrobenzoate, cesium 4-nitrobenzoate, beryllium 4-nitrobenzoate,magnesium 4-nitrobenzoate, calcium 4-nitrobenzoate, 4-fluorobenzoicacid, lithium 4-fluorobenzoate, sodium 4-fluorobenzoate, potassium4-fluorobenzoate, cesium 4-fluorobenzoate, beryllium 4-fluorobenzoate,magnesium 4-fluorobenzoate, and calcium 4-fluorobenzoate.

Alternative solvents can be dimethylsulfoxide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrolidine, 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, diisopropylether,acetone, methylethyl ketone, methylisobutylketone, diisopropyl ether,1,4-dioxane, 1,2-dimethoxyethane, chloroform, acetonitrile, toluene,dichloromethane, 1,2-dichloroethane, methanol, ethanol, n-propanol,2-propanol, butanol, tert-butanol, benzene, and nitromethane.

Temperatures can range from about 0° C. to about 5° C. or about −10° C.to about 100° C., and reaction times may range from about 30 minutes toabout 24 hours or about 30 minutes to about 4 hours.

Reaction of Compound (5-4) to Compound (5-5)

To3-(2-bromo-1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (5-4)) (8.0 g) in dichloromethane (181 mL) at about 2° C. wasadded a solution of pyridinium tribromide (7.7 g) in MeOH (8.1 mL).After complete conversion, the reaction mixture was extracted with water(23 mL) and aqueous hydrochloric acid (3.4% wt., 2×25 mL) to yield asolution containing the product,9-bromo-3-(2-bromo-1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (5-5)). HRMS (ESI⁺ MS/MS) Calculated for C₁₉H₁₇Br2O₃ m/z(M+H): 450.9544 and 452.9524; Found: 450.9524, and 452.9534; ¹H NMR (400MHz, CDCl₃) δ 7.75 (d, J=8.1 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.42(d, J=7.5 Hz, 1H), 7.24 (s, 1H), 5.13 (s, 2H), 4.99-4.96 (m, 1H), 4.73(dd, J=4.1, 4.1 Hz, 1H), 3.69-3.66 (m, 1H), 3.58-3.53 (m, 1H), 3.35-3.27(m, 1H), 2.96-2.90 (m, 1H), 2.58-2.44 (m, 2H), C—OH not observed.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, various brominating agents may beemployed, such as bromine, bromine monochloride, N-bromosuccinimide,5,5-dimethyl-1,3-dibromohydantoin,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric acid,tribromoisocyanuric acid, N-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N′-dibromo-4-methylbenzenesulphonamide, sodium bromate, lithiumbromate, potassium bromate, tetra-n-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, N-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin,3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione,dibromo(triphenyl)phosphorane, carbon tetrabromide, bromoform,dibromomethane, hexabromoacetone, lithium bromide, sodium bromide,potassium bromide, cesium bromide, beryllium bromide, magnesium bromide,calcium bromide, aluminum bromide, indium bromide, titanium bromide,ferrous bromide, ferric bromide, tin bromide, and hydrobromic acid.

Alternative solvents can include 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, diisopropylether,acetone, methylethyl ketone, methylisobutylketone, diisopropyl ether,1,4-dioxane, 1,2-dimethoxyethane, chloroform, acetonitrile, toluene,dichloromethane, 1,2-dichloroethane, ethanol, n-propanol, 2-propanol,butanol, tert-butanol, benzene, and nitromethane.

The reaction may take place at temperatures that range from about 0° C.to about 5° C. or about −10° C. to about 100° C. and at time lengths ofabout 30 minutes to about 4 hours or about 30 minutes to about 24 hours.

Reaction of Compound (5-5) to Compound (I-a)

A solution of9-bromo-3-(2-bromo-1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(approx. 3.2 g) (Compound (5-5)) in dichloromethane (60 mL) at about 20°C. was combined with sodium bicarbonate (0.8 g), sodium bromide (0.8 g),TEMPO (56 mg) and water (18 mL). The mixture was combined with anaqueous solution of sodium hypochlorite (10.3% wt., 9.4 mL). Aftercompletion of the reaction, isopropyl alcohol (9.1 mL) was addedfollowed by an aqueous solution of hydrochloric acid (10% wt., 4.3 mL).The mixture was filtered and the cake washed with water (29 mL) and a1:5 mixture of isopropyl alcohol and dichloromethane at about 5° C. Thesolids were collected and dried under vacuum to obtain9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (I-a)). HRMS (ESI⁺ MS/MS) Calculated for Chemical Formula:C₁₉H₁₅Br₂O₃ m/z (M+H): 448.9388 and 450.9367; Found: 448.9396, and450.9380. ¹H NMR (400 MHz, CDCl₃) δ 8.03-8.01 (m, 1H), 7.85 (d, J=8.2Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74(dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m,1H), 2.59-2.46 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 190.4, 189.6, 154.2,136.6, 134.1, 133.9, 132.9, 131.8, 129.3, 127.2, 125.6, 124.2, 123.3,117.0, 68.1, 49.9, 31.8, 30.4, 25.5.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative catalysts, in lieu ofTEMPO, may include tetrapropylammonium perruthenate,2-azaadamantane-N-oxyl, 1-methyl-2-azaadamantane-N-oxyl,1,3-dimethyl-2-azaadamantane-N-oxyl, and4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammoniumtetrafluoroborate.

Various oxidizing agents may be employed. Examples of oxidizing agentscan include diacetoxy iodobenzene, di(trifluoxoacetoxy) iodobenzene,dichloro iodobenzene, potassium persulfate, sodium perborate, sodiumbromate, sodium iodate, sodium periodate, urea hydrogen peroxide,tert-butylhydroperoxide, N-methylmorpholine-N-oxide,trimethylammonium-N-oxide, sodium dichloroisocyanuric acid,iodosobenzene, N-bromo succinimide, N-bromoacetamide,N-bromophthalimide, sodium bromite, sodium hypobromite,m-chloroperbenzoic acid, 2-iodoxybenzoic acid, ruthenium trichloride,rhodium(I) tris-(triphenylphosphine) chloride, palladium(II) acetate,titanium tetraisopropoxide, ferric bromide, copper(I) chloride,copper(II) chloride, copper(I) bromide, copper(II) bromide,tetrapropylammonium perruthenate, N-chloro succinimide,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, trimethylaluminium, aluminum triisopropoxide, dimethylsulfoxide, potassiumperoxymonosulfate, cericammonium nitrate, oxygen, trichloroisicyanuricacid, cromine, iodine, chlorine, bromine, bromine monochloride,5,5-dimethyl-1,3-dibromohydantoin, pyridinium tribromide,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric acid,tribromoisocyanuric acid, N-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N′-dibromo-4-methylbenzenesulphonamide, sodium bromate, lithiumbromate, potassium bromate, tetra-n-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, N-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin, and3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione,dibromo(triphenyl)phosphorane.

Alternative additives can include hydrobromic acid, lithium bromide,sodium bromide, potassium bromide, cesium bromide, beryllium bromide,magnesium bromide, calcium bromide, tetrabutylammonium bromide,tetraethylammonium bromide, tetramethyl bromide, pyridinium bromide,aluminum bromide, titanium bromide, indium bromide, ferric bromide,ferrous bromide, copper(I) bromide, copper(II) bromide, hydroiodic acid,lithium iodide, sodium iodide, potassium iodide, cesium iodide,beryllium iodide, magnesium iodide, calcium iodide, tetrabutylammoniumiodide, tetraethylammonium iodide, tetramethyl iodide, pyridiniumiodide, aluminum iodide, titanium iodide, indium iodide, ferric iodide,ferrous iodide, copper(I) iodide, and copper(II) iodide.

Various bases may be employed, such as lithium carbonate, sodiumcarbonate, cesium carbonate, beryllium carbonate, magnesium carbonate,calcium carbonate, strontium carbonate, barium carbonate, lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,beryllium hydroxide, magnesium hydroxide, calcium hydroxide, strontiumhydroxide, barium hydroxide, lithium bicarbonate, sodium bicarbonate,potassium bicarbonate, cesium bicarbonate, beryllium bicarbonate,magnesium bicarbonate, calcium bicarbonate, strontium bicarbonate,barium bicarbonate, lithium tert-butoxide, sodium tert-butoxide,potassium tert-butoxide, cesium tert-butoxide, beryllium tert-butoxide,magnesium tert-butoxide, calcium tert-butoxide, strontium tert-butoxide,barium tert-butoxide, trilithium phosphate, trisodium phosphate,tripotassium phosphate, tricesium phosphate, beryllium phosphate,magnesium phosphate, calcium phosphate, strontium phosphate, dilithiumhydrogenphosphate, disodium hydrogenphosphate, dipotassiumhydrogenphosphate, dicesium hydrogenphosphate, lithiumdihydrogenphosphate, sodium dihydrogenphosphate, potassiumdihydrogenphosphate, and cesium dihydrogenphosphate.

Alternative solvents can include 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, diisopropylether,acetone, methylethyl ketone, methylisobutylketone, diisopropyl ether,1,4-dioxane, 1,2-dimethoxyethane, chloroform, acetonitrile, toluene,dichloromethane, 1,2-dichloroethane, tert-butanol, benzene, andnitromethane.

The reaction may take place at temperatures that range from about 20° C.to about 25° C. or about 0° C. to about 40° C. and at time lengths ofabout 30 minutes to about 2 hours or about 0.2 hours to about 24 hours.

Example 6: Alternative Synthesis of Compound (I-a)

Reaction of Compound (5-4) to Compound (6)

To a 1 L reactor was charged3-(2-bromo-1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(25 g), (Compound (5-4)) dichloromethane (370 mL), and TEMPO (0.2 g).The mixture was cooled to about 2° C. A solution of sodium bicarbonate(7.4 g), sodium bromide (7.4 g) and water (130 mL) was charged and themixture agitated. The mixture was combined with an aqueous solution ofsodium hypochlorite (11.9% wt., 80 mL). After completion of thereaction, 2-propanol (40 mL) was charged and the mixture warmed to about25° C. A volume of about two-thirds of dichloromethane was removed underreduced pressure, the mixture cooled to about 5° C. and then filteredthrough a fritted funnel. The filter cake was washed twice with water(75 mL) and with dichloromethane (30 mL) and then dried at about 40° C.under reduced pressure to provide3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (6)). ¹H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.1 Hz, 1H), 8.01(d, J=8.1 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.81(s, 1H), 7.81 (s, 1H), 7.65 (s, 2H), 7.65 (s, 2H), 5.18 (s, 2H), 4.45(s, 2H), 3.08-2.91 (m, 2H), 2.75-2.59 (m, 2H), 2.26-2.07 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative catalysts can includetetrapropylammonium perruthenate, 2-azaadamantane-N-oxyl,1-methyl-2-azaadamantane-N-oxyl, 1,3-dimethyl-2-azaadamantane-N-oxyl,and 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammoniumtetrafluoroborate.

Various oxidizing agents may be employed. Non-limiting examples includediacetoxy iodobenzene, di(trifluoxoacetoxy) iodobenzene, dichloroiodobenzene, potassium persulfate, sodium perborate, sodium bromate,sodium iodate, sodium periodate, urea hydrogen peroxide,tert-butylhydroperoxide, N-methylmorpholine-N-oxide,trimethylammonium-N-oxide, sodium dichloroisocyanuric acid,iodosobenzene, N-bromo succinimide, N-bromoacetamide,N-bromophthalimide, sodium bromite, sodium hypobromite,m-chloroperbenzoic acid, 2-iodoxybenzoic acid, ruthenium trichloride,rhodium(I) tris-(triphenylphosphine) chloride, palladium(II) acetate,titanium tetraisopropoxide, ferric bromide, copper(I) chloride,copper(II) chloride, copper(I) bromide, copper(II) bromide,tetrapropylammonium perruthenate, N-chloro succinimide,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, trimethylaluminium, aluminum triisopropoxide, dimethylsulfoxide, potassiumperoxymonosulfate, cericammonium nitrate, oxygen, trichloroisicyanuricacid, cromine, iodine, chlorine, bromine, bromine monochloride,5,5-dimethyl-1,3-dibromohydantoin, pyridinium tribromide,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric acid,tribromoisocyanuric Acid, N-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N′-dibromo-4-methylbenzenesulphonamide, sodium bromate, lithiumbromate, potassium bromate, tetra-n-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, N-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin, and3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione, anddibromo(triphenyl)phosphorane.

Alternative additives may be employed, such as hydrobromic acid, lithiumbromide, sodium bromide, potassium bromide, cesium bromide, berylliumbromide, magnesium bromide, calcium bromide, tetrabutylammonium bromide,tetraethylammonium bromide, tetramethyl bromide, pyridinium bromide,aluminum bromide, titanium bromide, indium bromide, ferric bromide,ferrous bromide, copper(I) bromide, copper(II) bromide, hydroiodic acid,lithium iodide, sodium iodide, potassium iodide, cesium iodide,beryllium iodide, magnesium iodide, calcium iodide, tetrabutylammoniumiodide, tetraethylammonium iodide, tetramethyl iodide, pyridiniumiodide, aluminum iodide, titanium iodide, indium iodide, ferric iodide,ferrous iodide, copper (I) iodide, and copper (II) iodide.

Various bases may be employed, such as lithium carbonate, sodiumcarbonate, cesium carbonate, beryllium carbonate, magnesium carbonate,calcium carbonate, strontium carbonate, barium carbonate, lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,beryllium hydroxide, magnesium hydroxide, calcium hydroxide, strontiumhydroxide, barium hydroxide, lithium bicarbonate, sodium bicarbonate,potassium bicarbonate, cesium bicarbonate, beryllium bicarbonate,magnesium bicarbonate, calcium bicarbonate, strontium bicarbonate,barium bicarbonate, lithium tert-butoxide, sodium tert-butoxide,potassium tert-butoxide, cesium tert-butoxide, beryllium tert-butoxide,magnesium tert-butoxide, calcium tert-butoxide, strontium tert-butoxide,barium tert-butoxide, trilithium phosphate, trisodium phosphate,tripotassium phosphate, tricesium phosphate, beryllium phosphate,magnesium phosphate, calcium phosphate, strontium phosphate, dilithiumhydrogenphosphate, disodium hydrogenphosphate, dipotassiumhydrogenphosphate, dicesium hydrogenphosphate, lithiumdihydrogenphosphate, sodium dihydrogenphosphate, potassiumdihydrogenphosphate, and cesium dihydrogenphosphate.

Alternative solvents can be employed. Non-limiting examples can include2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,diethylether, diisopropylether, acetone, methylethyl ketone,methylisobutylketone, diisopropyl Ether, 1,4-dioxane,1,2-dimethoxyethane, chloroform, acetonitrile, toluene, dichloromethane,1,2-dichloroethane, tert-butanol, benzene, and nitromethane.

The reaction may take place at temperatures that range from about 20° C.to about 25° C. or about 0° C. to about 40° C. and at time lengths ofabout 30 minutes to about 2 hours or about 0.2 hours to about 6 hours.

Reaction of Compound (6) to Compound (I-a)

A mixture of3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.58g) (Compound (6)), pyridinium tribromide (2.56 g), dichloromethane (22mL) and methanol (2.5 mL) was stirred at ambient temperature for 3hours. The mixture was filtered, the filter cake washed withdichloromethane (10 mL) and then dried under reduced pressure at 40° C.to give9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (I-a)). HRMS (ESI⁺ MS/MS) Calculated for Chemical Formula:C₁₉H₁₅Br₂O₃ m/z (M+H): 448.9388 and 450.9367; Found: 448.9396, and450.9380. ¹H NMR (400 MHz, CDCl₃) δ 8.03-8.01 (m, 1H), 7.85 (d, J=8.2Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74(dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m,1H), 2.59-2.46 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, additional starting material in lieuof Compound (6) may be3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one and3-acetyl-9-bromo-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one.

Various brominating agents may be employed. Non-limiting examples caninclude bromine, bromine monochloride, N-bromosuccinimide,5,5-dimethyl-1,3-dibromohydantoin,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric acid,tribromoisocyanuric acid, N-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N′-dibromo-4-methylbenzenesulphonamide, sodium bromate, lithiumbromate, potassium bromate, tetra-n-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, N-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin,3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione,dibromo(triphenyl)phosphorane, carbon tetrabromide, bromoform,dibromomethane, hexabromoacetone, lithium bromide, sodium bromide,potassium bromide, cesium bromide, beryllium bromide, magnesium bromide,calcium bromide, aluminum bromide, indium bromide, titanium bromide,ferrous bromide, ferric bromide, tin bromide, and hydrobromic acid.

Alternative solvents may be 2-methyltetrahydrofuran, tetrahydrofuran,isopropyl acetate, ethyl acetate, tert-butyl methyl ether, cyclopentylmethyl ether, diethylether, diisopropylether, acetone, methylethylketone, methylisobutylketone, diisopropyl ether, 1,4-dioxane,1,2-dimethoxyethane, chloroform, acetonitrile, toluene, dichloromethane,1,2-dichloroethane, ethanol, n-propanol, 2-propanol, butanol,tert-butanol, benzene, and nitromethane.

The reaction may take place at temperatures that range from about 0° C.to about 5° C. or about −10° C. to about 100° C. and at time lengths ofabout 30 minutes to about 4 hours or about 30 minutes to about 24 hours.

Example 7: Alternative Synthesis of Compound (I-a)

Reaction of Compound (5-3) to Compound (7)

A reaction flask at ambient temperature was charged with3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (10.0 g)(Compound (5-3)), powdered anhydrous tripotassium phosphate (22.4 g),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (“XPhos”) (1.34g), and PdCl₂(MeCN)₂ (364 mg). Acetonitrile (140 mL) was added followedby trimethylsilylacetylene (18 mL). The mixture was heated to about 65°C. After about 6 h, the reaction was judged complete, and the mixturewas cooled to about 20° C. The mixture was drained and filtered througha fritted funnel, and the filter cake was washed with MeCN. The filtratewas concentrated to about 150 mL under reduced pressure and extractedwith heptane (50 mL, then 3×100 mL). N-Acetyl cysteine (15 g) was addedto the MeCN phase, and the mixture was agitated for about 5 h at about45° C. The mixture was cooled to about 23° C., filtered through afritted funnel, and the filter cake was washed with MeCN. The filtratewas concentrated to about 120 mL under reduced pressure. Water (120 mL)was added and the mixture was agitated for about 40 minutes at about 45°C. and then cooled to ambient temperature. After about 30 minutes themixture was filtered through a fritted funnel to provide3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (7)). MS (ESI⁺ MS/MS) Calculated for Chemical Formula:C₂₂H₂₃O₂Si m/z (M+H): 347.1467; Found: 347.1486. ¹H NMR (400 MHz, CDCl₃)δ 7.65 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.47 (dd, J=8.1,1.4 Hz, 1H), 7.27 (s, 1H), 5.06 (s, 2H), 2.95 (t, J=6.1 Hz, 2H),2.67-2.59 (m, 2H), 2.18-2.08 (m, 2H), 0.26 (s, 9H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative starting material, inlieu of 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, may becompounds of the following structures:

wherein R^(g) may be alkoxy, aryloxy, or heterocyclooxy. Otheralternative starting material can include3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-bromo-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-iodo-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yltrifluoromethanesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl benzenesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl4-methylbenzenesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl4-fluorobenzenesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl4-(trifluoromethyl)benzenesulfonate,8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylic acid,lithium8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, sodium8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,potassium8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, cesium8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, methyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, ethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, propyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,isopropyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, butyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,isobutyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,2,2,2-trifluoroethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, phenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,p-tolyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,4-nitrophenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,4-fluorophenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,4-(trifluoromethyl)phenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,4-methoxyphenyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,trifluoromethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate,difluoromethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate, andfluoromethyl8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-carboxylate.

Alternative metal components and ligand components of the catalyst maybe employed. Non-limiting examples of metal components can includepalladium(II) trifluoroacetate, palladium (II) acetylacetonate,allylpalladium(II) chloride dimer, palladium(II) acetate, palladium (II)pivalate, palladium(II) chloride, palladium (II) bromide,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium,bis(acetonitrile)dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct,tetrakis(triphenylphosphine)palladium(0),dichlorobis(tricyclohexylphosphine)palladium(II),bis(triphenylphosphine)palladium(II) dichloride,dichlorobis(tri-o-tolylphosphine)palladium(II),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane,[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II),tetrakis(acetonitrile)palladium(II) tetrafluoroborate, (SPhos)palladium(II) phenethylamine chloride, (XPhos) palladium(II)phenethylamine chloride, (RuPhos) palladium(II) phenethylamine chloride,(t-BuXPhos) palladium(II) phenethylamine chloride, and (BrettPhos)palladium(II) phenethylamine chloride.

Ligand components may be phosphines with at least one alkyl substituent.Non-limiting examples of ligand components may betri-(2-furyl)phosphine, tri-tert-butylphosphine, tri-tert-butylphosphinehydro tetrafluoroborate, methyl-di-tert-butylphosphine,methyl-di-tert-butylphosphine hydro tetrafluoroborate,4,5-bis(dicyclohexylphosphino)-9,9-dimethylxanthene,tri(cyclohexyl)phosphine, tri(2-furanyl)phosphine,1,1′-bis(diphenylphosphino) ferrocene, 1,1′-bis(dicyclohexylphosphino)ferrocene, 1,1′-bis(ditertbutylphosphino) ferrocene,1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride,1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride,1,3-diisopropylimidazolium tetrafluoroborate,1,3-bis(1-adamantyl)imidazolium tetrafluoroborate,2-(dicyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-Dicyclohexylphosphino-2′-methylbiphenyl,2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl,2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonatehydrate, 2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl,(2-biphenyl)di-tert-butylphosphine,2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-di-tert-butylphosphino-2′-methylbiphenyl,2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,2-Di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl,2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane,1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,1,5-bis(diphenylphosphino)pentane, 1,6-bis(diphenylphosphino)hexane,bis(dicyclohexylphosphino)methane, 1,2-bis(dicyclohexylphosphino)ethane,1,3-bis(dicyclohexylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,5-bis(dicyclohexylphosphino)pentane,1,6-bis(dicyclohexylphosphino)hexane, bis(diisopropylphosphino)methane,1,2-bis(diisopropylphosphino)ethane,1,3-bis(diisopropylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,5-bis(diisopropylphosphino)pentane,1,6-bis(diisopropylphosphino)hexane, bis(di-tert-butylphosphino)methane,1,2-bis(di-tert-butylphosphino)ethane,1,3-bis(di-tert-butylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,5-bis(di-tert-butylphosphino)pentane,1,6-bis(di-tert-butylphosphino)hexane,bis(dicyclopentylphosphino)methane,1,2-bis(dicyclopentylphosphino)ethane,1,3-bis(dicyclopentylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,5-bis(dicyclopentylphosphino)pentane,1,6-bis(dicyclopentylphosphino)hexane, and the like.

Various bases may also be employed, such as lithium carbonate, sodiumcarbonate, cesium carbonate, beryllium carbonate, magnesium carbonate,calcium carbonate, strontium carbonate, barium carbonate, lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,beryllium hydroxide, magnesium hydroxide, calcium hydroxide, strontiumhydroxide, barium hydroxide, lithium bicarbonate, sodium bicarbonate,potassium bicarbonate, cesium bicarbonate, beryllium bicarbonate,magnesium bicarbonate, calcium bicarbonate, strontium bicarbonate,barium bicarbonate, lithium hydride, sodium hydride, potassium hydride,magnesium hydride, calcium hydride, lithium tert-butoxide, sodiumtert-butoxide, potassium tert-butoxide, cesium tert-butoxide, berylliumtert-butoxide, magnesium tert-butoxide, calcium tert-butoxide, strontiumtert-butoxide, barium tert-butoxide, aluminum tert-butoxide, titaniumtert-butoxide, 2,2,6,6-tetramethylpiperidine, 2,6-ditertbutylpyridine,4-methyl-2,6-ditertbutylpyridine, trilithium phosphate, trisodiumphosphate, tripotassium phosphate, tricesium phosphate, berylliumphosphate, magnesium phosphate, calcium phosphate, strontium phosphate,dilithium hydrogenphosphate, disodium hydorgenphosphate, dipotassiumhydrogenphosphate, dicesium hydrogenphosphate, lithiumdihydrogenphosphate, sodium dihydrogenphosphate, potassiumdihydrogenphosphate, cesium dihydrogenphosphate, lithiumtert-butylcarboxylate, sodium tert-butylcarboxylate, potassiumtert-butylcarboxylate, cesium tert-butylcarboxylate, lithium acetate,sodium acetate, potassium acetate, cesium acetate, lithium propanoate,sodium propanoate, potassium propanoate, cesium propanoate, lithiumisobutyrate, sodium isobutyrate, potassium isobutyrate, cesiumisobutyrate, lithium adamantylcarboxylate, sodium adamantylcarboxylate,potassium adamantylcarboxylate, cesium adamantylcarboxylate, lithiumtrifluoroaceate, sodium trifluoroaceate, potassium trifluoroaceate,cesium trifluoroaceate, triethylamine, trimethylamine, tripropylamine,tributylamine, diisopropylethylamine, dicyclohexylmethylamine, lithiummethoxide, lithium ethoxide, lithium isopropoxide, lithium propoxide,lithium butoxide, lithium phenoxide, sodium methoxide, sodium ethoxide,sodium isopropoxide, sodium butoxide, sodium phenoxide, potassiummethoxide, potassium ethoxide, potassium isopropoxide, potassiumpropoxide, potassium butoxide, potassium phenoxide, cesium methoxide,cesium ethoxide, cesium isopropoxide, cesium propoxide, cesium butoxide,and cesium phenoxide.

Alternative solvents can include N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrolidine, 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, diisopropylether,acetone, methylethyl ketone, methylisobutylketone, diisopropyl ether,1,4-dioxane, 1,2-dimethoxyethane, chloroform, acetonitrile, toluene,dichloromethane, 1,2-dichloroethane dimethylsulfoxide, methanol,ethanol, n-propanol, 2-propanol, butanol, tert-butanol, benzene, andnitromethane.

The reaction may take place at temperatures that range from about 5° C.to about 100° C. and at time lengths of about 1 hour to about 48 hours.

Reaction of Compound (7) to Compound (K)

3-((Trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(850 mg) was combined with formic acid (9.8 mL) at about 23° C. Themixture was heated to about 65° C. After about 3 h, the reaction wasjudged complete. The mixture was concentrated under reduced pressure;the resulting residue was purified by chromatography on a silica gelcolumn eluting with a solvent gradient from 5% to 85% EtOAc/hexanes. Theproduct containing fractions were combined and concentrated to provide3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (Compound (K)):¹H NMR (400 MHz, CDCl₃) δ 8.00-7.94 (m, 1H), 7.81 (d, J=8.2 Hz, 1H),7.77 (s, 1H), 7.64 (s, 2H), 5.16 (s, 2H), 2.98 (t, J=6.1 Hz, 2H),2.69-2.64 (m, 2H), 2.63 (s, 3H), 2.21-2.09 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative starting material, inlieu of Compound (K), may be3-((triisopropylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-((triethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-((tert-butyldiphenylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-((methyldiphenylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(3-hydroxy-3-methylbut-1-ynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-ethynyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(1-methoxyvinyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(1-ethoxyvinyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(1-(2-hydroxyethoxy)vinyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(1-isopropoxyvinyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(1-propoxyvinyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(1-butoxyvinyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(1-bromovinyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(1-chlorovinyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(2-methyl-1,3-dioxan-2-yl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,3-(2-methyl-1,3-dioxepan-2-yl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one,and3-(2-methyl-1,3-dioxocan-2-yl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one.

Alternative acids may include formic acid, acetic acid, propanoic acid,butyric acid, isobutyric acid, pentanoic acid, pivalic acid,trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid,trichloroacetic acid, dichloroacetic acid, chloroacetic acid, benzoicacid, 4-nitrobenzoic acid, 4-fluorobenzoic acid, 4-chlorobenzoic acid,4-fromobenzoic acid, 4-iodobenzoic acid, 4-methylbenzoic acid,4-trifluoromethylbenzoic acid, phenol, 4-nitrophenol, 4-fluorophenol,4-chlorophenol, 4-bromophenol, 4-iodophenol, 4-trifluoromethylphenol,4-methylphenol, methylsulfonic acid, trifluoromethylsulfonic acid,benzenesulfonic acid, toluenesulfonic acid, 4-nitrobenzenesulfonic acid,4-fluorobenzenesulfonic acid, 4-chlorobenzenesulfonic acid,4-bromobenzenesulfonic acid, 4-iodobenzenesulfonic acid,4-trifluoromethylbenzenesulfonic acid, tetrafluoroboric acid,fluoroantimonic acid, hydrofluoric acid, hydrochloric acid, hydrobromicacid, hydroiodic acid, phosphoric acid, and sulfuric acid.

Various solvents may be employed. Non-limiting examples includeN,N-dimethylformamide, N-methylpyrolidine, 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, diisopropylether,acetone, methylethyl ketone, methylisobutylketone, diisopropyl ether,1,4-dioxane, 1,2-dimethoxyethane, chloroform, acetonitrile, toluene,dichloromethane, 1,2-dichloroethane dimethylsulfoxide, methanol,ethanol, n-propanol, 2-propanol, butanol, tert-butanol, benzene, andnitromethane.

The reaction may take place at temperatures that range from about 0° C.to about 100° C. and at time lengths of about 12 minutes to about 48hours.

Reaction of Compound (K) to Compound (I-a)

A reaction vessel at ambient temperature was charged with3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (100 mg)(Compound (K)), 9:1 CH₂Cl₂/MeOH (3.4 mL) and pyridinium tribromide (246mg). The solution was heated to about 35° C. After about 30 minutes, thereaction was judged complete. The mixture was cooled to about 23° C.,diluted with EtOAc (50 mL) and sequentially washed with saturatedaqueous Na₂S₂O₃ (20 mL), 2% aqueous NaHCO₃ (20 mL), water (20 mL), andbrine (10 mL). The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure resulting in9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (I-a)): ¹H NMR (400 MHz, CDCl₃) δ 8.03-8.01 (m, 1H), 7.85 (d,J=8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H),4.74 (dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92(m, 1H), 2.59-2.46 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of Compound (K), alternativestarting material may be3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (6)) or3-acetyl-9-bromo-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one.

Various brominating agents may be used. Non-limiting examples caninclude bromine, bromine monochloride, N-bromosuccinimide,5,5-dimethyl-1,3-dibromohydantoin,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric acid,tribromoisocyanuric acid, N-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N′-dibromo-4-methylbenzenesulphonamide, sodium bromate, lithiumbromate, potassium bromate, tetra-n-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, N-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin,3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione,dibromo(triphenyl)phosphorane, carbon tetrabromide, bromoform,dibromomethane, hexabromoacetone, lithium bromide, sodium bromide,potassium bromide, cesium bromide, beryllium bromide, magnesium bromide,calcium bromide, aluminum bromide, indium bromide, titanium bromide,ferrous bromide, ferric bromide, tin bromide, and hydrobromic acid.

Alternative solvents may be employed, such as dimethylsulfoxide,N,N-dimethylformamide, N-methylpyrolidine, 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, diisopropylether,acetone, methylethyl ketone, methylisobutylketone, diisopropyl ether,1,4-dioxane, 1,2-dimethoxyethane, chloroform, acetonitrile, toluene,dichloromethane, 1,2-dichloroethane, ethanol, n-propanol, 2-propanol,butanol, tert-butanol, benzene, and nitromethane.

The reaction may take place at temperatures that range from about 0° C.to about 60° C. and at time lengths of about 2 hours to about 5 hours orabout 12 minutes to about 24 hours.

Example 8: Alternative Synthesis of Compound (I-a)

Preparation of Compound (M-a) from Compound (8-1)

To a stirred solution of 2-bromo-5-iodobenzyl alcohol (5.0 g, 16.0 mmol)(Compound (8-1)) in dry THF (40 mL) was added a 2 M solution ofisopropylmagnesium chloride in THF (17.6 mL, 35.2 mmol) whilemaintaining the internal temperature below about −10° C. A whitesuspension was formed after 5 min. The mixture was stirred for about 1 hat or below about −10° C. and then was added N-methoxy-N-methylacetamide(3.73 mL, 35.2 mmol) dropwise over a period of about 3 min. The reactionmixture was allowed to warm to about 20° C. over 1 h. The reactionmixture was cooled to about 0° C., quenched with 3N HCl (25 mL), anddiluted with tert-butylmethyl ether (50 mL). The resulting biphasicmixture was stirred and the layers separated. The organic layer waswashed with 1M HCl (50 mL) followed by water (50 mL) and concentratedunder reduced pressure to afford Compound (M-a) as a crude productmixture which was used in next step without further purification. ¹H NMR(400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4Hz, 1H), 4.79 (s, 2H), 2.59 (s, 3H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative metalation reagents, inlieu of isopropylmagnesium chloride, can be magnesium metal,alkyllithium, or lithium metal, and alternative acylating reagents, inlieu of N-methoxy-N-methylacetamide, may be acetonitrile, acetylchloride or acetic anhydride. Various additives may be employed, such ashexamethylphosphoramide, N,N,N′,N′-tetramethylethylenediamine, andchlorotrimethylsilane. Various solvents, such as tetrahydrofuran,2-methyltetrahydrofuran, or mixtures of toluene and tetrahydrofuran maybe employed, and the reaction may proceed at temperatures of about −15°C. to about 20° C.

Alternative Preparation of Compound (M-a) Via Tert-ButyldimethylsilylEther Protection

Step A:

To a stirred solution of 2-bromo-5-iodobenzylalcohol (10 g, 32 mmol)(Compound (8-1)) in dichloromethane (200 mL) was added imidazolefollowed by TBDMS-Cl at room temperature. The mixture was stirred atroom temperature for about 2 h and partitioned between dichloromethane(additional 100 mL) and water (200 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give(2-bromo-5-iodobenzyloxy)(tert-butyl)dimethylsilane, Compound (8-2),which was used in next step without further purification.

Step B:

To a stirred solution of Compound (8-2) (12.5 g, 29.3 mmol) in dry THF(37.5 mL) was added a 2M solution of isopropylmagnesium chloride in THF(16.1 mL, 32.2 mmol) while maintaining the internal temperature below−20° C. The mixture was stirred for about 45 min at or below −20° C. andthen was added with N-methoxy-N-methylacetamide (3.73 mL, 35.2 mmol)dropwise over a period of about 3 min. The resulting mixture was allowedto warm to about 20° C. over about 1 h. The reaction mixture was cooledto about 0° C., quenched with saturated NH₄Cl (10 mL), diluted withtert-butylmethyl ether (100 mL), and washed with water (2×50 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to give1-(4-bromo-3-((tert-butyldimethylsilyloxy) methyl)phenyl)ethanone,Compound (8-3). The crude product was used in next step without furtherpurification.

Step C:

To a stirred solution of Compound (8-3) (11.42 g, 33.3 mmol) in THF (55L) was added a 2 M solution of HCl in water (33.3 mL) at roomtemperature and the mixture was stirred for about 3 h. The reactionmixture was partitioned between ethyl acetate and, sequentially,saturated sodium bicarbonate and water. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give Compound (M-a).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in Step B, alternative metalationreagents, in lieu of isopropylmagnesium chloride, may be magnesiummetal, alkyl lithium, or lithium metal, and alternative acylatingreagents, in lieu of N-methoxy-N-methylacetamide, may be acetonitrile,acetyl chloride or acetic anhydride. Various additives may be employed,such as hexamethylphosphoramide, N,N,N′,N′-tetramethylethylenediamine,and chlorotrimethylsilane. Various solvents, such as tetrahydrofuran or2-methyltetrahydrofuran, may be employed, and the reaction may proceedat temperatures of about −15° C. to about 20° C. The reaction mayproceed at time lengths of about 1 hour to about 5 hours.

In Step A, alternative protecting groups, such as trimethylsilyl,triethylsilyl, tert-butyldiphenylsilyl, tetrahydropyranyl, etc may beused. Depending on the protecting group used in Step A, an appropriatedeprotection conditions should be employed in Step C. Strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. The reactions in Steps A and C can proceed atabout 20° C. and at time lengths of about 2 hours to about 3 hours.

Preparation of Compound (M-b),1-(4-bromo-3-(chloromethyl)phenyl)ethanone

To a stirred solution of 1-(4-bromo-3-(hydroxymethyl)phenyl)ethanone(3.1 g, 13.5 mmol) in dry THF (30 mL) was added triethylamine (2.82 mL,20.25 mmol) and the mixture was cooled to about 0° C. Methanesulfonylchloride (1.15 mL, 14.9 mmol) was added to the cold mixture dropwiseover a period of about 3 min. The resultant mixture was stirred at about0° C. for about 30 min and then lithium chloride (2.9 g, 67.5 mmol) wasadded. The mixture was allowed to warm to room temperature and stirredfor about an additional 2 h. The reaction mixture was partitionedbetween tert-butylmethyl ether (30 mL) and water (2×15 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to a minimum volume. Heptane (15 mL) was added tothe residue and the mixture was gently stirred for about 2 h to give asuspension. The solids were collected by filtration, washed with heptane(5 mL) and dried under vacuum to give Compound (M-b). ¹H NMR (400 MHz,CDCl₃) δ 8.05 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H),4.73 (s, 2H), 2.60 (s, 3H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative reagents in lieu ofmethanesulfonyl chloride may be methanesulfonic anhydride. Alternativereagents for chlorination may be tosyl chloride/lithium chloride,thionyl chloride, and triphenylphosphine/N-chlorosuccinimide. Residualtriethylamine hydrochloride salt generated during mesylation reactionmay also be used as chlorinating agent without using lithium chloride.Various solvents may be employed, such as tetrahydrofuran and2-methyltetrahydrofuran. The reaction may take place at temperaturesthat range from about 0° C. to about 20° C. and at time lengths of about5 hours to about 7 hours.

Preparation of Compound (M-c), 1-(4-bromo-3-(bromomethyl)phenyl)ethanone

To a stirred solution of 1-(4-bromo-3-(hydroxymethyl)phenyl)ethanone(458 mg, 2 mmol) in dichloromethane (5 mL) was added triethylamine(0.417 mL, 3 mmol) and the mixture was cooled to about 0° C.Methanesulfonyl chloride (0.107 mL, 2.2 mmol) was added to the mixturedropwise and the stirred for about 1 h at about 0° C. The reactionmixture was partitioned between MTBE (25 mL) and water (2×10 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give the mesylate. To themesylate was added THF (5 mL) and lithium bromide (695 mg, 8 mmol) andthe mixture was stirred at room temperature for about 2 h. The reactionmixture was partitioned between MTBE (25 mL) and water (2×10 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give Compound (M-c). ¹H NMR (400MHz, CDCl₃) δ 8.02 (d, J=2.0 Hz, 1H), 7.74-7.68 (m, 2H), 4.63 (s, 2H),2.60 (s, 3H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative reagents in lieu ofmethanesulfonyl chloride may be methanesulfonic anhydride. Alternativereagents for bromination may include tosyl chloride/lithium bromide,thionyl bromide, triphenylphosphine/N-bromosuccinimide, phosphoroustribromide, triphenylphosphine/carbon tetrabromide, and hydrobromicacid. Various solvents may be employed, such as tetrahydrofuran and2-methyltetrahydrofuran. The reaction may take place at temperaturesthat range from about 0° C. to about 20° C. and at time lengths of about30 minutes to about 3 hours or about 30 minutes to about 1 hour.

Preparation of Compound (L-a),7-(5-acetyl-2-bromobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one

A mixture of 1-(4-bromo-3-(chloromethyl)phenyl)ethanone (600 mg, 2.42mmol), 7-hydroxytetralone (393 mg, 2.42 mmol), potassium carbonate (668mg, 4.84 mmol) and tetrabutylammonium bromide (78 mg, 0.242 mmol) inDMAc (3 mL) was stirred at room temperature for about 20 h. The reactionmixture was partitioned between ethyl acetate (18 mL) and water (2×6mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated to an approximate volume of 5 mL. Product precipitate wasfiltered, washed with ethyl acetate (2 mL) and dried under vacuum togive Compound (L-a). ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J=2.4 Hz, 1H),7.7 (dd, J=8.4, 2.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.64 (d, J=2.4 Hz,1H), 7.23-7.16 (m, 2H), 5.17 (s, 2H), 2.92 (t, J=6.4 Hz, 2H), 2.65 (dd,J=13.2, 6.0 Hz, 2H), 2.60 (s, 3H), 2.16-2.10 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, an alternative reagent may be sodiumiodide. Various solvents, such as tetrahydrofuran,2-methyltetrahydrofuran, N,N-dimethylformamide, and acetonitrile, may beemployed. The reaction may take place at a temperature of about 20° C.or at temperatures that range from about 20° C. to about 65° C. and maytake place at time lengths of about 6 hours to about 20 hours.

Alternative Preparation of Compound (L-a)

A mixture of 1-(4-bromo-3-(bromomethyl)phenyl)ethanone (500 mg, 1.71mmol), 7-hydroxytetralone (291 mg, 1.79 mmol), potassium carbonate (472mg, 3.42 mmol) and acetonitrile (5 mL) was heated at about 70° C. forabout 2 h. The mixture was partitioned between MTBE (20 mL) and water(2×10 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give crude product.Column chromatography of the crude mixture on silica gel using 15-50%ethyl acetate hexanes gradient followed by recrystallization frommethanol (3.5 mL) gave Compound (L-a).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, an alternative reagent may be sodiumiodide. Various solvents, such as tetrahydrofuran,2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide,and acetonitrile, may be employed. The reaction may take place attemperatures that range from about 20° C. to about 70° C.

Preparation of Compound (K),3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one

A reaction vessel was charged with7-(5-acetyl-2-bromobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (2.5 g,6.7 mmol) (Compound (L-a)), palladium (II) acetate (150 mg, 0.67 mmol),triphenylphosphine (175.5 mg, 0.67 mmol), pivalic acid (205 mg, 2.01mmol), potassium carbonate (1.02 g, 7.37 mmol) and DMAc (50 mL). Thereaction vessel was evacuated and back filled with nitrogen. Thereaction mixture was then heated at about 80° C. under nitrogenatmosphere for about 5 h. After completion of the reaction the mixturewas cooled to room temperature and charged with ethyl acetate (50 mL)followed by water (75 mL). The biphasic mixture was stirred at roomtemperature for about 20 min and filtered through a pad of celite andpartitioned. The organic layer was washed with water (25 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure to anapproximate final volume of 10 mL. The product precipitated wascollected by filtration, washed with ice cold ethyl acetate (5 mL) anddried under vacuum to give Compound (K). ¹H NMR (400 MHz, DMSO-d6) δ8.05 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.90 (s,1H), 7.36 (s, 1H), 5.21 (s, 2H), 2.95 (t, J=5.6 Hz, 1H), 2.61-2.56 (m,3H), 2.59 (s, 3H), 2.05-2.02 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative reagents may includetetrabutyl ammonium bromide, Pd(dba)₂, P(4-FPh)₃, KHCO₃, and DMF.Various solvents may be used, such as DMF and acetonitrile. In addition,the reaction may be performed in the absence of triphenylphosphine. Thereaction may also take place at temperatures that range from about 20°C. to about 80° C. and at time lengths of about 5 hours to about 7hours.

Preparation of Compound (I-a)

To a stirred solution of Compound (K) (100 mg, 0.342 mmol) in 9:1dichloromethane/methanol mixture (2 mL) was added pyridinium tribromide(250 mg, 90% technical grade, 0.718 mmol) at room temperature and themixture was stirred for about 5 h. Product precipitated was filtered,washed with methanol (1 mL) and dried under vacuum to give Compound(I-a). ¹H NMR (400 MHz, DMSO-d6) δ 8.17-8.01 (m, 3H), 8.01-7.92 (m, 1H),7.43 (s, 1H), 5.24 (s, 2H), 5.05 (dd, J=8.0 and 4.0 Hz, 1H), 4.94 (s,2H), 3.15-3.00 (m, 2H), 2.63-2.55 (m, 1H), 2.41-2.35 (m, 1H).

Alternative reagents and reaction conditions may also be employed asdescribed in Example 7. Catalytic HBr can be used for the earlyinitiation of bromination reaction.

Example 9: Synthesis to Compound (I-b)

To a reaction vessel was charged Compound (I-a) (10 g) and a solution oftetrahydrofuran and water (10 vol:1 vol; 500 mL). The reactor contentswere agitated and sodium chloride (26 g) was added. The internaltemperature was adjusted to about 40° C. After complete conversion, thereaction mixture was concentrated under reduced pressure and the residuefiltered. The filter cake was washed with water (200 mL) and suspendedin dichloromethane (120 mL) at about 30° C. After about 12 h, themixture was cooled to about 2° C. and filtered. The filter cake waswashed with water (300 mL) and dried under reduced pressure at about 40°C. to Compound (I-b). ¹H NMR (400 MHz, CDCl₃) δ 8.00 (m, 1H), 7.86 (m,1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 5.20 (s, 2H), 4.74 (m,1H), 4.70 (s, 2H), 3.40-3.27 (m, 1H), 2.96 (m, 1H), 2.60-2.44 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative reagents, in lieu ofsodium chloride, may be lithium chloride, potassium chloride, cesiumchloride, beryllium chloride, magnesium chloride, calcium chloride, andbarium chloride. various solvents may be employed. non-limiting examplesmay include dimethylsulfoxide, N,N-dimethylformamide,N-methylpyrolidine, 2-methyltetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,diethylether, diisopropylether, acetone, methylethyl ketone,methylisobutylketone, diisopropyl ether, 1,4-dioxane,1,2-dimethoxyethane, chloroform, acetonitrile, toluene, dichloromethane,1,2-dichloroethane, ethanol, n-propanol, 2-propanol, butanol,tert-butanol, benzene, and nitromethane. The reaction may proceed attemperatures ranging from about 0° C. to about 60° C. and for timelengths of about 16 hours or about 30 minutes to about 48 hours.

Example 10: Alternative Synthesis to Compound (I-a)

Preparation of Compound (K) from Compound (O)

Conversion of Compound (O) to Compound (K) may be carried out in thepresence of palladium (such asdichloro[2-(4,5-dihydro-2-oxazolyl)quinoline]palladium(II)) withtert-butylhydroperoxide as an oxidizing agent, silver tetrafluoroborateas an additive, and a mixture of DMF and water as a solvent. Thereaction may take place at about 20° C. to about 70° C. and for timelengths of about 30 minutes to about 24 hours.

Alternatively, the conversion of Compound (O) to Compound (K) may becarried out in the presence of palladium catalyst (such asbis(acetonitrile)dichloropalladium(II) or palladium(II)chloride) withoxygen as an oxidizing agent, and a mixture of DMAc and water as asolvent. The reaction may take place at about 20° C. to about 80° C. andfor time lengths of about 30 minutes to about 24 hours.

Alternative reagents and reaction conditions to those disclosed abovemay also be contemplated. Alternative palladium catalysts may bepalladium(II) trifluoroacetate, palladium (II) acetylacetonate,allylpalladium(II) chloride dimer, palladium (II) acetate, palladium(II)pivalate, palladium (II) chloride, palladium (II) bromide,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium,bis(acetonitrile)dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct,tetrakis(triphenylphosphine)palladium(0),dichlorobis(tricyclohexylphosphine)palladium(II),bis(triphenylphosphine)palladium(II) dichloride,dichlorobis(tri-o-tolylphosphine)palladium(II),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane,[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II),tetrakis(acetonitrile)palladium(II) tetrafluoroborate, copper(I)chloride, copper(II) chloride, copper(I) bromide, copper(II) bromide,copper(I) iodide, copper(II) iodide, copper(I) triflate, copper(II)triflate, copper(I) oxide, copper(II) oxide, copper(I)tetrafluoroborate, copper(II) tetrafluoroborate, copper(I)hexafluoroantimonate, and copper(II) hexafluoroantimonate.

Various ligands may be employed, including but not limited to(S)-2-(4,5-dihydro-4-isopropyl-2-oxazolyl)quinoline,2-(4,4-dimethyl-4,5-dihydro-2-oxazolyl)quinoline,1,3-Bis-(2,6-diisopropylphenyl)imidazolinium chloride,1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride,1,3-diisopropylimidazolium tetrafluoroborate,1,3-bis(1-adamantyl)imidazolium tetrafluoroborate,1,3-bis(2,6-diisopropylphenyl)imidazolium chloride, sparteine,ethylenediamine, tetramethylethylenediamine, and Troger's base.

Alternative oxidizing agents may include oxygen, hydrogenperoxide, ureahydrogen peroxide, palladium(II) reagents, copper(I) iodide, copper(II)iodide, copper(I) triflate, copper(II) triflate, copper(I) oxide,copper(II) oxide, copper(I) tetrafluoroborate, copper(II)tetrafluoroborate, copper(I) hexafluoroantimonate, copper(II)hexafluoroantimonate, diacetoxy iodobenzene, di(trifluoxoacetoxy)iodobenzene, dichloro iodobenzene, potassium persulfate, sodiumperborate, sodium bromate, sodium iodate, sodium periodate, ureahydrogen peroxide, tert-butylhydroperoxide, N-methylmorpholine-N-oxide,trimethylammonium-N-oxide, sodium dichloroisocyanuric acid,iodosobenzene, N-bromo succinimide, N-bromoacetamide,N-bromophthalimide, sodium bromite, sodium hypobromite,m-chloroperbenzoic acid, 2-iodoxybenzoic acid, ruthenium trichloride,rhodium(I) tris-(triphenylphosphine) chloride, palladium(II) acetate,titanium tetraisopropoxide, ferric bromide, copper(I) chloride,copper(II) chloride, copper(I) bromide, copper(II) bromide,tetrapropylammonium perruthenate, N-chloro succinimide,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, trimethylaluminium, aluminum triisopropoxide, dimethylsulfoxide, potassiumperoxymonosulfate, cericammonium nitrate, oxygen, trichloroisicyanuricacid, cromine, iodine, chlorine, bromine, bromine monochloride,5,5-dimethyl-1,3-dibromohydantoin, pyridinium tribromide,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric Acid,tribromoisocyanuric Acid, N-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N′-dibromo-4-methylbenzenesulphonamide, sodium bromate, lithiumbromate, potassium bromate, tetra-n-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, N-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin,3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione, anddibromo(triphenyl)phosphorane.

Alternative additives may be employed. Non-limiting examples may besilver nitrate, silver hexafluoroantimonate, copper(I) triflate,copper(II) triflate, copper(I) oxide, copper(II) oxide, copper(I)tetrafluoroborate, copper(II) tetrafluoroborate, copper(I)hexafluoroantimonate, and copper(II) hexafluoroantimonate.

The reaction can take place in various solvents, such asdimethylsulfoxide, N,N-dimethylformamide, N-methylpyrolidine,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,diethylether, diisopropylether, acetone, methylethyl ketone,methylisobutylketone, diisopropyl ether, 1,4-dioxane,1,2-dimethoxyethane, chloroform, acetonitrile, toluene, dichloromethane,1,2-dichloroethane, methanol, ethanol, n-propanol, 2-propanol, butanol,tert-butanol, benzene, nitromethane, and water.

The reaction may proceed at temperatures ranging from about 0° C. to100° C. and at time lengths of about 30 minutes to about 48 hours.

Preparation of Compound (I-a) from Compound (K)

A reaction vessel at ambient temperature was charged with3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (100 mg), 9:1CH₂Cl₂/MeOH (3.4 mL) and pyridinium tribromide (246 mg). The solutionwas heated to about 35° C. After about 30 minutes, the reaction wasjudged complete. The mixture was cooled to about 23° C., diluted withEtOAc (50 mL) and sequentially washed with saturated aqueous Na₂S₂O₃ (20mL), 2% aqueous NaHCO₃ (20 mL), water (20 mL), and brine (10 mL). Theorganic phase was dried over MgSO₄, filtered and concentrated underreduced pressure to afford9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(Compound (I-a)). ¹H NMR (400 MHz, CDCl₃) δ 8.03-8.01 (m, 1H), 7.85 (d,J=8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H),4.74 (dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92(m, 1H), 2.59-2.46 (m, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative starting material may be3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one or3-acetyl-9-bromo-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one.

Various brominating agents may be used. Non-limiting examples caninclude bromine, bromine monochloride, N-bromosuccinimide,5,5-dimethyl-1,3-dibromohydantoin,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric acid,tribromoisocyanuric acid, n-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N′-dibromo-4-methylbenzenesulphonamide, sodium bromate, lithiumbromate, potassium bromate, tetra-N-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, n-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin,3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione,dibromo(triphenyl)phosphorane, carbon tetrabromide, bromoform,dibromomethane, hexabromoacetone, lithium bromide, sodium bromide,potassium bromide, cesium bromide, beryllium bromide, magnesium bromide,calcium bromide, aluminum bromide, indium bromide, titanium bromide,ferrous bromide, ferric bromide, tin bromide, and hydrobromic acid.

Various solvents may be employed, such as dimethylsulfoxide,N,N-dimethylformamide, N-methylpyrolidine, 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, diethylether, diisopropylether,acetone, methylethyl ketone, methylisobutylketone, diisopropyl ether,1,4-dioxane, 1,2-dimethoxyethane, chloroform, acetonitrile, toluene,dichloromethane, 1,2-dichloroethane, ethanol, n-propanol, 2-propanol,butanol, tert-butanol, benzene, and nitromethane.

The reaction may proceed at temperatures ranging from about 0° C. to 60°C. and at time lengths of about 12 minutes to about 24 hours.

Example 11: Alternative Synthesis to Compound (I-a)

Preparation of Compound (P-a) from Compound (5-3)

To synthesize Compound (P-a) from Compound (5-3), Compound (5-3) can bereacted in the presence of a catalyst, such as Pd(OAc)₂, a ligand suchas 1,3-diisopropylphosphinopropane, and a base such as triethylamine.The solvent for the reaction may be N,N-dimethylacetamide. The reactiontemperature may be from about 20° C. to about 80° C., and the reactiontime may range from about 20 minutes to about 2 hours. The reaction maybe conducted in the presence of a stabilizer such as3,5-di-tert-butyl-4-hydroxytoluene.

Alternative reagents and reaction conditions to those disclosed abovemay also be contemplated. For example, alternative catalysts may includepalladium(II) trifluoroacetate, palladium(II) acetylacetonate,allylpalladium(II) chloride dimer, palladium(II) acetate, palladium(II)pivalate, palladium(II) chloride, palladium(II) bromide,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium,bis(acetonitrile)dichloropalladium(II),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct,tetrakis(triphenylphosphine)palladium(0),dichlorobis(tricyclohexylphosphine)palladium(II),bis(triphenylphosphine)palladium(II) dichloride,dichlorobis(tri-o-tolylphosphine)palladium(II),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane,[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II),tetrakis(acetonitrile)palladium(II) tetrafluoroborate, (SPhos)palladium(II) phenethylamine chloride, (XPhos) palladium(II)phenethylamine chloride, (RuPhos) palladium(II) phenethylamine chloride,(t-BuXPhos) palladium(II) phenethylamine chloride, and (BrettPhos)palladium(II) phenethylamine chloride.

Alternative ligands, in lieu of 1,3-diisopropylphosphinopropane, may beany ligands known in the art. Non-limiting examples may betriphenylphosphine, tri-(2-furyl)phosphine, Tri-tert-butylphosphine,tri-tert-butylphosphine hydro tetrafluoroborate,methyl-di-tert-butylphosphine, methyl-di-tert-butylphosphine hydrotetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,tri(p-tolyl)phosphine, 4-(methoxy)phenyldiphenylphosphine,4-(dimethylamino)phenyldiphenylphosphine, tri(4-fluorophenyl)phosphine,tri(4-trifluoromethylphenyl)phosphine, tri(4-methoxyphenyl)phosphine,tri(3-methylphenyl)phosphine, tri(2-methylphenyl)phosphine,tri(cyclohexyl)phosphine, tri(2-furanyl)phosphine,1,1′-bis(diphenylphosphino) ferrocene, 1,1′-bis(dicyclohexylphosphino)ferrocene, 1,1′-bis(ditertbutylphosphino) ferrocene,1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride,1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride,1,3-diisopropylimidazolium tetrafluoroborate,1,3-bis(1-adamantyl)imidazolium tetrafluoroborate,2-(dicyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′-methylbiphenyl,2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl,2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonatehydrate, 2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl,(2-biphenyl)di-tert-butylphosphine,2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-di-tert-butylphosphino-2′-methylbiphenyl,2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl,2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane,1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,1,5-bis(diphenylphosphino)pentane, 1,6-bis(diphenylphosphino)hexane,bis(dicyclohexylphosphino)methane, 1,2-bis(dicyclohexylphosphino)ethane,1,3-bis(dicyclohexylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,5-bis(dicyclohexylphosphino)pentane,1,6-bis(dicyclohexylphosphino)hexane, bis(diisopropylphosphino)methane,1,2-bis(diisopropylphosphino)ethane,1,3-bis(diisopropylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,5-bis(diisopropylphosphino)pentane,1,6-bis(diisopropylphosphino)hexane, bis(di-tert-butylphosphino)methane,1,2-bis(di-tert-butylphosphino)ethane,1,3-bis(di-tert-butylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,5-bis(di-tert-butylphosphino)pentane,1,6-bis(di-tert-butylphosphino)hexane,bis(dicyclopentylphosphino)methane,1,2-bis(dicyclopentylphosphino)ethane,1,3-bis(dicyclopentylphosphino)propane,1,3-bis(dicyclohexylphosphino)propane,1,5-bis(dicyclopentylphosphino)pentane,1,6-bis(dicyclopentylphosphino)hexane, and the like.

Alternative alkenes may be 1-(vinyloxy)methane, 1-(vinyloxy)ethane,1-(vinyloxy)propane, 1-(vinyloxy)-2-propane, tert-butyl vinyl ether,ethylene glycol vinyl ether, isobutyl vinyl ether, vinyl acetate,tri(ethylene glycol) divinyl ether, 1,4-butanediol vinyl ether,di(ethylene glycol) vinyl ether, di(ethylene glycol) divinyl ether,isooctyl vinyl ether, 2-ethylhexyl vinyl ether,N,N-dimethyl-2-(vinyloxy)ethanamine, vinyl propionate, vinyl pivalate,cyclohexyl vinyl ether, 2,2,2-trifluoroethyl vinyl ether, vinylbutyrate, and vinyl trifluoroacetate.

Various bases may be employed. Non-limiting examples may include lithiumcarbonate, sodium carbonate, cesium carbonate, beryllium carbonate,magnesium carbonate, calcium carbonate, strontium carbonate, bariumcarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide,cesium hydroxide, beryllium hydroxide, magnesium hydroxide, Calciumhydroxide, strontium hydroxide, barium hydroxide, lithium bicarbonate,sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, berylliumbicarbonate, magnesium bicarbonate, calcium bicarbonate, strontiumbicarbonate, barium bicarbonate, lithium hydride, sodium hydride,potassium hydride, magnesium hydride, calcium hydride, lithiumtert-butoxide, sodium tert-butoxide, potassium tert-butoxide, cesiumtert-butoxide, beryllium tert-butoxide, magnesium tert-butoxide, calciumtert-butoxide, strontium tert-butoxide, barium tert-butoxide, aluminumtert-butoxide, titanium tert-butoxide, 2,2,6,6-tetramethylpiperidine,2,6-ditertbutylpyridine, 4-methyl-2,6-ditertbutylpyridine, trilithiumphosphate, trisodium phosphate, tripotassium phosphate, tricesiumphosphate, beryllium phosphate, magnesium phosphate, calcium phosphate,strontium phosphate, dilithium hydrogenphosphate, disodiumhydorgenphosphate, dipotassium hydrogenphosphate, dicesiumhydrogenphosphate, lithium dihydrogenphosphate, sodiumdihydrogenphosphate, potassium dihydrogenphosphate, cesiumdihydrogenphosphate, lithium tert-butylcarboxylate, sodiumtert-butylcarboxylate, potassium tert-butylcarboxylate, cesiumtert-butylcarboxylate, lithium acetate, sodium acetate, potassiumacetate, cesium acetate, lithium propanoate, sodium propanoate,potassium propanoate, cesium propanoate, lithium isobutyrate, sodiumisobutyrate, potassium isobutyrate, cesium isobutyrate, lithiumadamantylcarboxylate, sodium adamantylcarboxylate, potassiumadamantylcarboxylate, cesium adamantylcarboxylate, lithiumtrifluoroaceate, sodium trifluoroaceate, potassium trifluoroaceate,cesium trifluoroaceate, triethylamine, trimethylamine, tripropylamine,tributylamine, diisopropylethylamine, dicyclohexylmethylamine, lithiummethoxide, lithium ethoxide, lithium isopropoxide, lithium propoxide,lithium butoxide, lithium phenoxide, sodium methoxide, sodium ethoxide,sodium isopropoxide, sodium butoxide, sodium phenoxide, potassiummethoxide, potassium ethoxide, potassium isopropoxide, potassiumpropoxide, potassium butoxide, potassium phenoxide, cesium methoxide,cesium ethoxide, cesium isopropoxide, cesium propoxide, cesium butoxide,and cesium phenoxide.

Various solvents may be employed, such as N,N-dimethylformamide,N-methylpyrolidine, 2-methyltetrahydrofuran, tetrahydrofuran, isopropylacetate, ethyl acetate, tert-butyl methyl ether, cyclopentyl methylether, diethylether, diisopropylether, acetone, methylethyl ketone,methylisobutylketone, diisopropyl ether, 1,4-dioxane,1,2-dimethoxyethane, chloroform, acetonitrile, toluene, dichloromethane,1,2-dichloroethane, dimethylsulfoxide, methanol, ethanol, n-propanol,2-propanol, butanol, tert-butanol, benzene, and nitromethane.

The reaction temperature may range from about 20° C. to about 100° C.,and the reaction time may range from about 30 minutes to about 48 hours.

Preparation of Compound (K) from Compound (P-a)

To synthesize Compound (K) from Compound (P-a), Compound (P-a) may bereacted with trifluoroacetic acid in a solvent of a mixture ofdichloromethane and water. The reaction may take place at about 5° C. toabout 40° C., and the reaction time may range from about 30 minutes toabout 12 hours.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative acids may be employed.Non-limiting examples may include formic acid, acetic acid, propanoicacid, butanoic acid, pivalic acid, pentanoic acid, benzoic acid,hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid,sulfuric acid, sulfurous acid, phosphoric acid, citric acid, nitricacid, oxalic acid, and the like. various solvents may be employed,including but not limited to N,N-dimethylformamide, N-methylpyrolidine,2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethylacetate, tert-butyl methyl ether, cyclopentyl methyl ether,diethylether, diisopropylether, acetone, methylethyl ketone,methylisobutylketone, diisopropyl ether, 1,4-dioxane,1,2-dimethoxyethane, chloroform, acetonitrile, toluene, dichloromethane,1,2-dichloroethane dimethylsulfoxide, methanol, ethanol, n-propanol,2-propanol, butanol, tert-butanol, benzene, nitromethane, and water.

The reaction temperature may range from about 0° C. to about 100° C.,and the reaction time may range from about 30 minutes to about 48 hours.

Preparation of Compound (I-a) from Compound (K)

Compound (I-a) may be synthesized from Compound (K) as described inExamples 7 and 8.

Example 12: Alternative Synthesis to Compound (I-a)

Preparation of Compound (I-a) from Compound (P-a)

Compound (I-a) may be synthesized from Compound (P-a) in the presence ofa brominating agent, such as pyridinium tribromide, and in a solvent,such as a mixture of dichloromethane and methanol. The reaction may takeplace from about 0° C. to about 40° C., and the reaction time may befrom about 20 minutes to about 2 hours.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative starting material may beCompound (6) or3-acetyl-9-bromo-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one.

Various brominating agents may be employed. Non-limiting examples caninclude bromine, bromine monochloride, N-bromosuccinimide,5,5-dimethyl-1,3-dibromohydantoin,2,4,4,6-tetrabromo-2,5-cyclohexadienone, dibromoisocyanuric acid,tribromoisocyanuric acid, N-bromoisocyanuric acid monosodium salt,N-bromo phthalimide, N-bromo acetamide,N,N-dibromo-4-methylbenzenesulfonamide, sodium bromate, lithium bromate,potassium bromate, tetra-n-butylammonium tribromide,trimethylphenylammonium tribromide, trimethylammonium tribromide,triethylammonium tribromide, bromine on polymer support,4-(dimethylamino)pyridine tribromide, pyridinium tribromide polymerbound, bromotrichloromethane, sodium hypobromite, lithium hypobromite,potassium hypobromite, beryllium hypobromite, magnesium hypobromite,calcium hypobromite, N,N-dibromobenzenesulfonamide, sodium bromite,lithium bromite, potassium bromite, N-bromo glutarimide,1,3-dibromo-2,4-imidazolidinedione,3-bromo-1-chloro-5,5-dimethylhydantoin,1-bromo-5-ethyl-3,5-dimethyl-2,4-imidazolidinedione,1,3-dibromo-5-ethyl-5-methylhydantoin,1,3-dibromo-5-isopropyl-5-methylhydantoin,3-bromo-5-methyl-5-phenyl-imidazolidine-2,4-dione,dibromo(triphenyl)phosphorane, carbon tetrabromide, bromoform,dibromomethane, hexabromoacetone, lithium bromide, sodium bromide,potassium bromide, cesium bromide, beryllium bromide, magnesium bromide,calcium bromide, aluminum bromide, indium bromide, titanium bromide,ferrous bromide, ferric bromide, tin bromide, and hydrobromic acid.

Alternative solvents may be dimethylsulfoxide, N,N-dimethylformamide,N-methylpyrolidine, 2-methyltetrahydrofuran, tetrahydrofuran, isopropylacetate, ethyl acetate, tert-butyl methyl ether, cyclopentyl methylether, diethylether, diisopropylether, acetone, methylethyl ketone,methylisobutylketone, diisopropyl ether, 1,4-dioxane,1,2-dimethoxyethane, chloroform, acetonitrile, toluene, dichloromethane,1,2-dichloroethane, ethanol, n-propanol, 2-propanol, butanol,tert-butanol, benzene, and nitromethane.

The reaction temperature may range from about 0° C. to about 60° C., andthe reaction time may range from about 12 minutes to about 24 hours.

Example 13: Synthesis of Compound (A)

1^(st) Alkylation: Conversion of Compound (I-a) to Compound (G-a)

Compound (I-a) (45 g, 1.0 equiv.), Compound (J-a) (26.7 g, 1.03 equiv.)and potassium carbonate (20.7 g, 1.5 equiv.) in dichloromethane (450 mL)were stirred at about 20° C. for approximately 3-4 hours. After thecompletion of the reaction, water (450 mL) was charged into the reactorand the mixture was stirred. Layers were separated, and the aqueouslayer was extracted with dichloromethane (200 mL). The combined organiclayers were washed with 2 wt % NaH₂PO4/10 wt % NaCl solution (450 mL).The organic layer was then concentrated and the solvent was swapped fromdichloromethane into tetrahydrofuran. A purified sample of Compound(G-a) has the following spectrum: ¹H NMR (400 MHz, CDCl₃) δ 7.90-7.94(m, 1H), 7.81-7.85 (m, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H),5.19-5.56 (2dd, 2H), 5.17 (s, 2H), 4.73 (t, 1H), 4.39-4.48 (m, 1H),3.70-3.77 (m, 1H), 3.37-3.45 (m, 2H), 3.33-3.35 (d, 3H), 3.28-3.32 (m,1H), 3.20-3.25 (dd, 1H), 2.92-2.96 (dt, 1H), 2.44-2.59 (m, 4H),1.97-2.09 (m, 1H), 1.44 (d, 9H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative starting material may beCompound (I) where X may be —Cl, —Br, —OTs, —OSO₂Ph, —OSO₂Me, —OSO₂CF₃,—OSO₂R, and —OP(O)(OR)₂ and Y may be —Cl, —Br, —OTs, —OSO₂Ph, —OSO₂Me,—OSO₂CF₃, —OSO₂R, and —OP(O)(OR)₂. R may be alkyl, haloalkyl, or anoptionally substituted aryl.

Various bases may also be employed, such as phosphate salts (includingbut not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄, and Na₃PO₄) and carbonatesalts (including but not limited to Na₂CO₃, Cs₂CO₃, and NaHCO₃). Wherethe starting material is Compound (J), KHCO₃ or preformed potassium,sodium, and cesium salts of Compound (J) may also be used.

Alternative solvents can include 2-methyltetrahydrofuran,tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methylether, cyclopentyl methyl ether, dimethylformamide, acetone, MEK, andMIBK.

The reaction temperature may range from about 10° C. to about 60° C.

2^(nd) Alkylation: Conversion of Compound (G-a) to Compound (B-a):

A solution of Compound (G-a) (prepared as described earlier startingfrom 45 g of Compound (I-a)) was mixed with Compound (H) (42.9 g, 1.5equiv.), and cesium carbonate (26.1 g, 0.8 equiv.). The reaction mixturewas stirred at about 40-45° C. until reaction was complete and thencooled to about 20° C. Water (450 mL) and ethyl acetate (225 mL) wereadded and the mixture was agitated. Layers were separated, and theaqueous layer was extracted with ethyl acetate (150 mL). Combinedorganic phase was concentrated and solvent was swapped to toluene. Apurified sample of Compound (B-a) has the following spectrum: ¹H NMR(400 MHz, CDCl₃) δ7.90-7.93 (m, 1H), 7.81-7.83 (m, 1H), 7.73 (s, 1H),7.63-7.64 (d, 1H), 7.59-7.60 (d, 1H), 5.52-5.63 (m, 1H), 5.30-5.43 (q,1H), 5.13-5.23 (s+m, 3H), 4.56-4.64 (m, 2H), 4.39-4.48 (m, 1H),4.20-4.27 (m, 1H), 3.62-3.79 (m, 2H), 3.66 (s, 2H), 3.36-3.45 (m, 2H),3.34-3.35 (d, 3H), 3.07-3.25 (m, 3H), 2.59-2.37 (m, 5H), 1.97-2.16 (m,3H), 1.60 (s, 3H), 1.38-1.45 (m, 12H), 0.91-1.03 (m, 6H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative starting material mayinclude Compound (G) where Y may be —Cl, —Br, —OTs, —OSO₂Ph, —OSO₂Me,—OSO₂CF₃, —OSO₂R, or —OP(O)(OR)₂. where R is alkyl, aryl, or substitutedaryl. In some embodiments, the substituted aryl may be an aryl havingone or more substituents, such as alkyl, alkoxy, hydroxyl, nitro,halogen, and others as discussed above.

Various bases may be employed. Non-limiting examples can includephosphate salts (including but not limited to KH₂PO₄, K₃PO₄, Na₂HPO₄,and Na₃PO₄) and carbonate salts (including but not limited to K₂CO₃ orNa₂CO₃). If Compound (H) is used as the starting material, Li₂CO₃ orpreformed potassium, sodium, and cesium salt of Compound (H) may beemployed.

Alternative solvents may include 2-methyltetrahydrofuran,dichloromethane, toluene, mixtures of THF/Toluene, isopropyl acetate,ethyl acetate, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, acetone,MEK, and MIBK. An alternative additive may be potassium iodide, and thereaction temperature may range from about 40° C. to about 60° C. orabout 40° C. to about 50° C.

Cyclization: Conversion of Compound (B-a) to Compound (C-a)

A toluene solution of Compound (B-a) (604 g solution from 45 g ofCompound (I-a)) was charged to a reaction vessel containing ammoniumacetate (185.2 g) and isopropanol (91.0 g). The contents of the reactorwere agitated at about 90° C. until the reaction was complete (about 16to 24 hours). The reaction mixture was cooled to about 45° C., and thenallowed to settle for layer separation. Water (226 g) was added to theorganic phase, and the resulting mixture was separated at about 30° C.Methanol (274 g), Celite (26.9 g) and an aqueous solution of sodiumhydroxide (67.5 g, 50%) and sodium chloride (54.0 g) in water (608 g)were added to the organic phase, and the resulting mixture was agitatedfor a minimum of 30 minutes. The mixture was then filtered throughCelite and rinsed forward with a mixture of toluene (250 g) andisopropanol (11 g). The biphasic filtrate was separated and water (223g) was added to the organic phase, and the resulting mixture wasagitated at about 30° C. for at least 15 minutes. The mixture wasfiltered through Celite and rinsed forward with toluene (91 g). Theorganic layer was concentrated by vacuum distillation to 355 g and wasadded over 30 minutes to another reactor containing n-heptane (578 g).The resulting slurry is filtered, with the wetcake was washed withn-heptane (450 mL) and dried in a vacuum oven to afford Compound (C-a).A purified sample of Compound (C-a) has the following spectrum: ¹H NMR(400 MHz, CDCl₃) δ 12.27-11.60 (m, 1H), 11.18-10.69 (m, 1H), 7.83-7.44(m, 4H), 7.36 (d, J=7.9 Hz, 1H), 7.28-7.05 (m, 1H), 5.65-5.25 (m, 1H),5.25-4.83 (m, 4H), 4.34-4.03 (m, 2H), 3.93-3.63 (m, 4H), 3.52 (s, 1H),3.35 (d, J=2.4 Hz, 4H), 3.19-2.94 (m, 4H), 2.88 (dd, J=12.0, 7.9 Hz, 3H), 2.66-1.85 (m, 5H), 1.79 (s, 5H), 1.37-1.12 (m, 6H), 1.04-0.98 (m,6H), 0.82 (t, J=7.7 Hz, 2H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative reagents, in lieu ofammonium acetate, can include hexamethyldisilazane, ammonia, ammoniumformate, ammonium propionate, ammonium hexanoate, and ammoniumoctanoate. Various solvents, such as toluene, xylene, an alcohol(including but not limited to isopropanol, 1-propanol, 1-butanol,2-butanol, 2-methoxyethanol, and glycols, such as ethylene glycol andpropylene glycol) may be employed. Alternative catalyst/additives mayinclude magnesium stearate, acetic acid, propionic acid, and aceticanhydride. The reaction temperature may range from about 60° C. to about110° C. or about 85° C. to about 95° C.

Dehydrogenation: Conversion of Compound (C-a) to Compound (D-a):

Preparation of Compound (D-a) Using DDQ as Oxidant:

A solution of Compound (C-a) (255.84 g) in 2-methyltetrahydrofuran (1535mL) was cooled to about 0° C. and acetic acid (0.92 mL) was added. Tothis mixture was added a solution of DDQ (76.98 g) in2-methyltetrahydrofuran (385 mL) over about 30 minutes. Upon reactioncompletion, a 10 wt % aqueous potassium hydroxide solution (1275 mL) wasadded over about 30 minutes and the mixture was warmed to about 20° C.Celite (101.5 g) was added and the slurry was filtered through Celite(50.0 g) and the filter cake was rinsed with 2-methyltetrahydrofuran(765 mL). The phases of the filtrate were separated. The organic phasewas washed successively aqueous potassium hydroxide solution (1020 mL,10 wt %), aqueous sodium bisulfate solution (1020 mL, 10 wt %), aqueoussodium bicarbonate solution (1020 mL, 5 wt %) and aqueous sodiumchloride solution (1020 mL, 5 wt %). The organic phase was thenconcentrated to a volume of about 650 mL. Cyclopentyl methyl ether (1530mL) was added and the resulting solution was concentrated to a volume ofabout 710 mL. The temperature was adjusted to about 40° C. and Compound(D-a) seed (1.0 g) was added. The mixture was agitated until a slurryforms, then methyl tert-butyl ether (2300 mL) was added over about 3hours. The slurry was cooled to about 20° C. over about 2 hours andfiltered. The filter cake was rinsed with methyl tert-butyl ether (1275mL) and dried in a vacuum oven at about 40° C. to provide Compound(D-a). A purified sample of Compound (D-a) has the following spectrum:¹H NMR (400 MHz, CDCl₃) δ 13.05-10.50 (comp m, 2H), 8.65-6.95 (comp m,8H), 5.50-5.35 (m, 2H), 5.25-4.60 (comp m, 3H), 4.35-4.20 (m, 1H),4.00-3.65 (comp m, 4H), 3.60-3.45 (m, 1H), 3.45-3.25 (comp m, 4H),3.25-3.00 (comp m, 2H), 2.95-1.65 (comp m, 6H), 1.47 (br s, 9H),1.40-1.25 (comp m, 2H), 1.20-0.70 (comp m, 9H).

Alternative Preparation of Compound (D-a) Using MnO₂ as Oxidant:

A mixture of Compound (C-a) (50.0 g), manganese (IV) oxide (152.8 g) anddichloromethane (500 mL) is stirred at about 20° C. Upon completion ofthe reaction, Celite (15 g) was added. The resulting slurry was filteredthrough Celite (20 g) and the filter cake was rinsed withdichloromethane (500 mL). The filtrate was concentrated and solventexchanged into cyclopentyl methyl ether (250 mL). The resulting solutionwas warmed to about 60° C. and treated with an aqueous potassiumhydroxide solution (250 mL, 10 wt %). The biphasic mixture is stirred atabout 45° C. for about 12 hours. The phases are then separated and theorganic phase is concentrated to a volume of about 150 mL. Theconcentrate is filtered, seeded with Compound (D-a) seed and agitated atabout 40° C. to obtain a slurry. Methyl tert-butyl ether (450 mL) wasadded to the slurry over 30 minutes and the resulting mixture was cooledto about 20° C. The precipitated solid was filtered, rinsed with methyltert-butyl ether (250 mL) and dried in a vacuum oven at about 40° C. toobtain Compound (D-a).

Alternative Preparation of Compound (D-a) Through CatalyticDehydrogenation

A mixture of Compound (C-a) (2.5 g, 2.7 mmol, 1 equiv), 5% Pd/Al₂O₃ (2.5g) and 1-propanol (25 mL, degassed) was stirred at reflux under inertenvironment for about 5.5 hours. The reaction mixture was then cooled toambient temperature and filtered through Celite, and the residue rinsedwith 1-propanol (2×5 mL) to obtain a solution of Compound (D-a).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in a reaction scheme employingstoichiometric oxidants, alternative oxidants may include manganese(IV)oxide, copper(II) acetate, copper(II) trifluoroacetate, copper(II)chloride, copper(II) bromide, bromine (Br₂), iodine (I₂),N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide,1,4-benzoquinone, tetrachloro-1,4-benzoquinone (chloranil), cericammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide,di-tert-butyl peroxide, benzoyl peroxide, oxygen (O₂), sodiumhypochlorite, sodium hypobromite, tert-butyl hypochlorite, Oxone,diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene. Variousadditives may be employed, and non-limiting examples may be carbonatebases (e.g., potassium carbonate, potassium bicarbonate, sodiumcarbonate, sodium bicarbonate, and the like), amines (e.g.,triethylamine, diisopropylethylamine and the like), and acids (e.g.,trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloricacid, sulfuric acid, phosphoric acid, para-toluenesulfonic acid,methanesulfonic acid), sodium acetate, potassium acetate, and the like).The reaction temperature may range from about −10° C. to 80° C. Thereaction may take place in solvents, such as halogenated solvents (e.g.,dichloromethane, 1,2-dichloroethane, etc.), aromatic solvents (e.g.,toluene, xylenes, etc.), ethereal solvents (tetrahydrofuran,1,4-dioxane, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme,triglyme, etc.), alcoholic solvents (e.g., methanol, ethanol,n-propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol,ethylene glycol, propylene glycol, etc.), ester solvents (e.g., ethylacetate, isopropyl acetate, tert-butyl acetate, etc.), ketone solvents(e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), polar aproticsolvents (e.g., acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethylsulfoxide, etc.), amine solvents (e.g., triethylamine, morpholine,etc.), acetic acid, and water.

In reaction schemes employing catalytic oxidants, alternative catalystsmay include palladium catalysts (e.g., palladium(II) acetate,palladium(II) trifluoroacetate, palladium(II) chloride, palladium(II)bromide, palladium(II) iodide, palladium(II) benzoate, palladium(II)sulfate, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(tri-tert-butylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,bis(acetonitrile)palladium(II) chloride, bis(benzonitrile)palladium(II)chloride, palladium on carbon, palladium on alumina, palladium onhydroxyapatite, palladium on calcium carbonate, palladium on bariumsulfate, palladium(II) hydroxide on carbon), platinum catalysts (e.g.,platinum on carbon, platinum(IV) oxide, chloroplatinic acid, potassiumchloroplatinate), rhodium catalysts (e.g., rhodium on carbon, rhodium onalumina, bis(styrene)bis(triphenylphosphine)rhodium(0)), rutheniumcatalysts (e.g., ruthenium(II) salen, dichloro(para-cymene)ruthenium(II)dimer), iridium catalysts (e.g., iridium(III) chloride,(1,5-cyclooctadiene)diiridium(I) dichloride,bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate,bis(triphenylphosphine)(1,5-cyclooctadiene)iridium(I) carbonyl chloride,bis(triphenylphosphine)(1,5-cyclooctadiene)iridium(I)tetrafluoroborate), copper catalysts (e.g., copper(I) chloride,copper(II) chloride, copper(I) bromide, copper(II) bromide, copper(I)iodide, copper(II) iodide, copper(II) acetate, copper(II)trifluoroacetate, copper(I) trifluoromethanesulfonate, copper(II)trifluoromethanesulfonate, copper(II) sulfate), iron catalysts (e.g.,iron(II) sulfate, iron(II) chloride, iron(III) chloride), vanadiumcatalysts (e.g., dichloro(ethoxy)oxovanadium,dichloro(isopropoxy)oxovanadium), manganese catalysts (e.g.,manganese(IV) oxide, manganese(III) (salen) chloride), cobalt catalysts(e.g., cobalt(II) acetate, cobalt(II) chloride, cobalt(II) salen),indium(III) chloride, silver(I) oxide, sodium tungstate, quinonecatalysts (e.g., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,1,4-benzoquinone, and tetrachloro-1,4-benzoquinone (chloranil)).

Alternative co-oxidants can include, but are not limited to, sodiumnitrite, copper(II) acetate, sodium persulfate, potassium persulfate,ammonium persulfate, sodium perborate, nitrobenzenesulfonate,2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), pyridine-N-oxide, hydrogenperoxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, benzoylperoxide, oxygen (O₂), sodium hypochlorite, sodium hypobromite,tert-butyl hypochlorite, oxone, diacetoxyiodobenzene, andbis(trifluoroacetoxy)iodobenzene.

Various hydrogen acceptors may be employed. Non-limiting examples caninclude unsaturated hydrocarbons (e.g., tert-butylethylene, tert-butylacetylene, 2-hexyne, cyclohexene, and the like), acrylate esters (e.g.,methyl acrylate, ethyl acrylate, isopropyl acrylate, tert-butylacrylate, and the like), maleate esters (e.g., dimethyl maleate, diethylmaleate, diisopropyl maleate, dibutyl maleate, and the like), fumarateesters (e.g., dimethyl fumarate, diethyl fumarate, diisopropyl fumarate,dibutyl fumarate, and the like), and quinones (e.g. chloranil,1,4-benzoquinone, etc.).

Alternative additives may be employed, such as carbonate bases (e.g.,potassium carbonate, potassium bicarbonate, sodium carbonate, sodiumbicarbonate, etc.), amine bases (e.g., triethylamine,diisopropylethylamine, etc.), phosphines (e.g., triphenylphosphine,tri(ortho-tolyl)phosphine, tricyclohexylphosphine, tri-n-butylphosphine,tri-tert-butylphosphine, etc.), acids (e.g., trifluoroacetic acid,trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid,phosphoric acid, para-toluenesulfonic acid, methanesulfonic acid, etc.),sodium acetate, N-hydroxyphthalimide, salen, 2,2′-bipyridine,9,10-phenanthroline, and quinine.

The reaction can proceed at temperatures ranging from about 10° C. toabout 120° C. Various solvents can be employed, including but notlimited to halogenated solvents (e.g., dichloromethane,1,2-dichloroethane, and the like), aromatic solvents (e.g., toluene,xylenes, and the like), ethereal solvents (tetrahydrofuran, 1,4-dioxane,cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme, triglyme, andthe like), alcoholic solvents (e.g., methanol, ethanol, n-propanol,isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, ethyleneglycol, propylene glycol, and the like), ester solvents (e.g., ethylacetate, isopropyl acetate, tert-butyl acetate, and the like), ketonesolvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, and thelike), polar aprotic solvents (e.g., acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone,pyridine, dimethyl sulfoxide, and the like), amine solvents (e.g.,triethylamine, morpholine, and the like), acetic acid, and water.

Deprotection: Conversion of Compound (D-a) to Compound (E-a):

Acetyl chloride (135 mL, 5 equiv.) was added slowly to methanol (750 mL)under external cooling maintaining reaction temperature below 30° C. Theresulting methanolic hydrogen chloride solution was cooled to about 20°C., and added slowly over about 1 hour to a solution of Compound (D-a)(300 g, 1 equiv.) in methanol (750 mL) held at about 60° C., and rinsedforward with methanol (300 mL). The reaction mixture was agitated atabout 60° C. until reaction was complete (about 1 hour), and then cooledto about 5° C. The reaction mixture was adjusted to pH 7-8 by additionof sodium methoxide (25 wt. % solution in methanol, 370 mL) over about20 minutes while maintaining reaction temperature below about 20° C.Phosphoric acid (85 wt. %, 26 mL, 1 equiv.) and Celite (120 g) wereadded to the reaction mixture, which was then adjusted to about 20° C.,filtered, and the filter cake was rinsed with methanol (1050 mL). Thecombined filtrate was polish filtered and treated with phosphoric acid(85 wt. %, 104 mL, 4 equiv.). The mixture was adjusted to about 60° C.,seeded with Compound (E-a) seed crystals (1.5 g), aged at about 60° C.for 4 hours and cooled slowly to about 20° C. over about 7.5 hours. Theprecipitated product was filtered, washed with methanol (2×600 mL), anddried in a vacuum oven at about 45° C. to provide Compound (E-a). ¹H NMR(400 MHz, D₂O) δ 7.53-6.77 (comp m, 8H), 5.24-4.80 (comp m, 3H),4.59-4.38 (comp m, 2H), 4.15-3.90 (m, 1H), 3.65-3.38 (comp m, 5H),3.36-3.14 (comp m, 4H), 2.75 (s, 1H), 2.87-2.66 (m, 1H), 2.29-1.60 (compm, 6H), 1.27 (d, 3H), 0.76 (m, 6H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. Various deprotection agents are well known tothose skilled in the art and include those disclosed in T. W. Greene &P. G. M. Wuts, Protective Groups in Organic Synthesis (4th edition) J.Wiley & Sons, 2007, hereby incorporated by reference in its entirety.For example, a wide range of acids may be used, including but notlimited to phosphoric acid, trifluoroacetic acid, p-toluenesulfonicacid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, thionyl chloride,and trimethylsilyl chloride. A wide range of solvents may be employed,including but not limited to water, ethanol, acetonitrile, acetone,tetrahydrofuran, 1,4-dioxane, and toluene. Deprotection may proceed attemperatures ranging from about 20° C. to about 110° C. or from about55° C. to about 65° C.

A wide range of bases may be employed as a neutralization reagent.Non-limiting examples can include sodium phosphate dibasic, potassiumphosphate dibasic, potassium bicarbonate, lithium hydroxide, sodiumhydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, and 4-methylmorpholine. Various solvents may beused for neutralization, such as water, ethanol, 1-propanol, 2-propanol,1-butanol, 2-butanol, acetone, acetonitrile, 2-butanone,4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, ethyl acetate, isopropyl acetate, dichloromethane, anddichloroethane. Neutralization may proceed at temperatures ranging fromabout −20° C. to about 60° C. or about 5° C. to about 15° C.

Various crystallization reagents can be employed. Non-limiting examplesmay be hydrochloric acid, hydrobromic acid, sulfuric acid,ethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid,oxalic acid, and glucuronic acid. Solvents for crystallization caninclude, but is not limited to, water, ethanol, 1-propanol, 2-propanol,and acetonitrile. Crystallization may proceed at temperatures rangingfrom about −20° C. to about 100° C.

Free-Basing of Compound (E-a) to Prepare Compound (E)

Compound (E-a) (10.0 g, 10.1 mmol) was dissolved in water (100 g) andthen dichloromethane (132 g) and 28% ammonium hydroxide (7.2 g) wereadded sequentially. The biphasic mixture was stirred for 45 minutes.Celite (2.2 g) was added, the mixture was filtered through a bed ofadditional Celite (5.1 g), and the phases were then separated. The lowerorganic phase was washed with water (50 g), filtered, and thenconcentrated by rotary evaporation to produce Compound (E). ¹H NMR (400MHz, CD₃OD) δ 8.35-7.17 (m, 8H), 5.6-4.68 (m, 3H), 4.41-3.96 (m, 2H),3.96-3.72 (br s, 1H), 3.74-3.48 (m, 2H), 3.42 (d, 2H), 3.33 (s, 3H),3.28 (s, 1H), 3.19-3.01 (m, 1H), 3.00-2.79 (m, 1H), 2.69-1.82 (m, 6H),1.80-1.45 (m, 3H), 1.21-0.73 (m, 8H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, tris-hydrochloride salts of Compound(E) may be used. Various bases may be employed, such as sodiumcarbonate, potassium carbonate, sodium hydroxide, and potassiumhydroxide. Various solvents, such as 2-methyltetrahydrofuran and ethylacetate, may be employed. The temperature may range from about 15° C. toabout 25° C.

Alternative Free-Basing of Compound (E-b) to Prepare Compound (E)

Compound (E-b) (15.2 g) was dissolved in water (100 g) and thendichloromethane (132 g) and 28% ammonium hydroxide (7.4 g) were addedsequentially. The biphasic mixture was stirred for about 45 minutes.Celite (2.1 g) was added, the mixture was filtered through a bed ofadditional Celite (5.2 g), and the phases were then separated. The lowerorganic phase was washed with water (50 g), filtered, and thenconcentrated by rotary evaporation to produce Compound (E). ¹H NMR (400MHz, CD₃OD) δ 7.92-6.73 (m, 8H), 5.51-4.90 (m, 2H), 4.63-4.30 (m, 3H),4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m,3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).

Salt Conversion of Compound (E-a) to Compound (E-b)

A solution of Compound (E-a) (10.0 g, 10.1 mmol), a solution of 37% HCl(10 g) in water (20 g), and acetonitrile (30 g) was warmed to about 50°C. and agitated for about 1 h. The solution was cooled to about 20° C.and acetonitrile (58 g) was charged to the reactor during which time aslurry formed. The slurry was stirred for about 21 h and then additionalacetonitrile (39 g) was added. The slurry was cooled to about 0° C.,held for about 60 min and the solids were then isolated by filtration,rinsed with 7% (w/w) water in acetonitrile (22 g) previously cooled toabout 5° C. The wet cake was partially deliquored to afford Compound(E-b). ¹H NMR (400 MHz, D₂O) δ 7.92-6.73 (m, 8H), 5.51-4.90 (m, 2H),4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m,4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55(m, 7H).

Coupling Reaction of Compound (E) and Compound (F) to Prepare Compound(A)

A flask was charged sequentially with2-chloro-4,6-bis[3-(perfluorohexyl)propyloxy]-1,3,5-triazine (“CDMT”)(2.2 giv) and methanol (8.9 g) and the slurry was cooled to about 0° C.To the mixture was added NMM (1.3 g) over about 5 minutes, maintainingan internal temperature of less than 20° C. The solution was stirred forabout 20 minutes to produce a solution of4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride inmethanol.

To a solution of Compound (E) (7.1 g) in dichloromethane (170 g) wasadded Compound (F) (2.8 g). The solution of4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride inmethanol was added over 2 minutes followed by a rinse of methanol (1.1g). After about 2.5 h, the completed reaction solution was washedsequentially with aqueous 10% potassium bicarbonate solution (40 mL), 3%hydrochloric acid (40 mL), and aqueous 10% potassium bicarbonatesolution (40 mL). The lower organic phase was washed with water (40 mL),filtered, and then concentrated by rotary evaporation to produceCompound (A). ¹H NMR (400 MHz, CD₃OD) δ 8.56-6.67 (m, 13H), 5.76-4.94(m, 4H), 4.86-4.67 (m, 1H), 4.47-3.98 (m, 1H), 3.98-2.72 (m, 15H),2.74-1.77 (m, 7H), 1.77-1.40 (m, 2H), 1.39-0.53 (m, 8H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, tris-phosphate salts ortris-hydrochloride salts of Compound (G) may be used as alternativestarting material. The reaction may take place at a temperature range offrom about 10° C. to about 20° C. Alternative coupling agents include,but are not limited to, EDC/HOBt, HATU, HBTU, TBTU, BOP, PyClOP, PyBOP,DCC/HOBt, COMU, EDCI/Oxyma, T3P, and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumtetrafluoroborate. An alternative bases that may be employed can bediisopropylethylamine. The reaction may proceed in DMF and attemperatures ranging from about −20° C. to about 30° C.

Salt Formation and Crystallization of Compound (A) Crystallization ofCompound (A-a)

A flask was charged with Compound (A) (10 g) and ethanol (125 mL) andwas then warmed to about 45° C. Concentrated hydrochloric acid (2.3 mL)was added followed by Compound (A-a) seed crystals (5 mg). The mixturewas cooled to about 20° C. over about 5 h and held for about anadditional 11 h. The solids were isolated by filtration, washed withethanol (2×20 mL), and deliquored to produce Compound (A-a). ¹H NMR (400MHz, CD₃OD) δ 8.94-7.22 (m, 14H), 5.78-5.11 (m, 5H), 4.53-4.04 (m, 1H),3.99-3.57 (m, 10H), 3.57-3.41 (m, 2H), 2.99-2.24 (m, 5H), 2.24-1.85 (m,3H), 1.80-1.50 (m, 2H), 1.39-0.73 (m, 8H).

Alternative Crystallization of Compound (A-b)

A reaction vessel was charged with Compound (A) (25.0 g) followed byethanol (125 mL) and 10% H₃PO₄ (250 mL). The solution was seeded withCompound (A-b) (100 mg) and stirred for about 17.5 h. The solids wereisolated by filtration, washed with ethanol (2×5 mL), deliquored, anddried in a vacuum oven to produce Compound (A-b). ¹H NMR (400 MHz, D₂O)δ 7.76-6.48 (m, 13H), 5.53-4.90 (m, 3H), 4.60-4.32 (m, 2H), 4.29-3.76(m, 1H), 3.70-2.75 (m, 14H), 2.66-1.51 (m, 8H), 1.51-1.09 (m, 3H),1.05-0.45 (m, 7H).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative acids may be hydrochloricacid, hydrobromic acid, L-tartaric acid. Various solvents may beemployed, such as methanol, ethanol, water, and isopropanol. Thereaction may proceed at temperatures ranging from about 5° C. to about60° C.

Free-Basing of Compound (A) Free-Basing of Compound (A-a) to PrepareCompound (A)

A reaction vessel was charged with Compound (A-a) (18.2 g) followed byethyl acetate (188 g) and 10% potassium bicarbonate (188 g) and themixture was stirred for about 25 minutes. The phases were separated andthe upper organic phase was then washed with water (188 mL). Theresulting organic solution was concentrated, ethanol (188 g) was added,and the solution was evaporated to produce a concentrate (75 g). Theresulting concentrate added into water (376 g) to produce a slurry. Thesolids were isolated by filtration, washed with water (38 g), deliquoredand dried in a vacuum oven at about 50° C. to produce Compound (A).

Alternative Free-Basing of Compound (A-b) to Prepare Compound (A)

A reaction vessel was charged with Compound (A-b) (3.0 g) followed byEtOAc (15 mL) and 10% KHCO₃ (15 mL) and agitation was initiated. Afterabout 5 h, the phases were separated and the organic phase was washedwith water (15 mL) and then concentrated by rotary evaporation undervacuum. The residue was taken up in EtOH (4.5 mL) and then added towater (30 mL) to produce a slurry. After about 15 min, the solids wereisolated by filtration rinsing forward water (3×3 mL). The solids weredried at about 50 to 60° C. vacuum oven for about 15 h to produceCompound (A).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, an alternative base may be ammoniumhydroxide or dibasic potassium phosphate. Various solvents may beemployed, such as ethanol and water. The reaction may proceed attemperatures ranging from about 15° C. to about 25° C.

The present disclosure is not to be limited in scope by the specificembodiments disclosed in the examples, which are intended to beillustrations of a few embodiments of the disclosure, nor is thedisclosure to be limited by any embodiments that are functionallyequivalent within the scope of this disclosure. Indeed, variousmodifications of the disclosure in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims. To this end, it shouldbe noted that one or more hydrogen atoms or methyl groups can be omittedfrom the drawn structures consistent with accepted shorthand notation ofsuch organic compounds, and that one skilled in the art of organicchemistry would readily appreciate their presence. All patents andpublications cited herein are hereby incorporated by reference in theirentirety.

1.-55. (canceled)
 56. A method for preparing a compound of formula(I-a), stereoisomer thereof, or mixture of stereoisomers thereof:

comprising the steps of: (a) cyclizing a compound of formula (L):

under conditions sufficient to yield a compound of formula (K):

and (b) brominating the compound of formula (K) under conditionssufficient to yield a compound of formula (I-a), wherein Z is hydrogen,halo, —OSO₂R¹, —BF₃ ⁻, —B(OR²)₂, —CO₂H, or —NR¹ ₃ wherein R¹ is alkyl,haloalkyl, aryl or substituted aryl, and R² is alkyl.
 57. The method ofclaim 56, wherein the reaction conditions of step (a) comprise a solventselected from the group consisting of N,N-dimethylacetamide,N,N-dimethylformamide, and acetonitrile.
 58. The method of claim 56,wherein the reaction conditions of step (a) comprise a temperature offrom about 20° C. to about 80° C.
 59. The method of claim 56, whereinthe reaction conditions of step (a) comprise at least one of a palladiumcatalyst, a carbonate salt, and a phosphine reagent.
 60. The method ofclaim 56, wherein the reaction conditions of step (b) comprise abrominating reagent selected from the group consisting ofpyridiniumtribomide, bromine, and N-bromosuccinimide.
 61. The method ofclaim 56, wherein the reaction conditions of step (b) comprise a solventselected from the group consisting of dichloromethane, methanol, and amixture thereof.
 62. The method of claim 56, wherein the reactionconditions of step (b) comprise a temperature of about 20° C.
 63. Themethod of claim 56, wherein the compound of formula (L):

is prepared by contacting a compound of formula (M):

with a compound of formula (N):

under conditions sufficient to yield the compound of formula (L),wherein X¹ is a leaving group, Y¹ is hydrogen, halo ortrifluoromethanesulfonate, and Z is hydrogen, halo, —OSO₂R¹, —BF₃ ⁻,—B(OR²)₂, —CO₂H, or —NR¹ ₃ wherein R¹ is alkyl, haloalkyl, aryl,substituted aryl, heteroaryl, or substituted heteroaryl, and R² isalkyl.
 64. The method of claim 63, wherein X¹ is halo, —OH, or —S(O)₂R³,and R³ is alkyl, haloalkyl, or aryl, and the aryl is optionallysubstituted with halo, alkyl, or haloalkyl.
 65. The method of claim 63,wherein the reaction conditions comprise a solvent selected from thegroup consisting of N,N-dimethylacetamide, tetrahydrofuran,2-methyltetrahydrofuran, N,N-dimethylformamide, and aceteonitrile. 66.The method of claim 63, wherein the reaction conditions comprise atemperature of from about 20° C. to about 70° C. 67.-134. (canceled)135. A compound of formula (L):

wherein Z is hydrogen, halo, —OSO₂R¹, —BF₃ ⁻, —B(OR²)₂, —CO₂H, or —NR¹ ₃wherein R¹ is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl, and R² is alkyl.
 136. The compound of claim 135,wherein Z is bromo.
 137. (canceled)
 138. The method of claim 63 wherethe compound of formula (M):

is prepared by reacting a compound of formula (M′):

with isopropylmagnesium chloride in THF and N-methoxy-N-methyl acetamideto form formula (M); wherein X¹ is a leaving group and Y¹ is hydrogen,halo or trifluoromethanesulfonate.